Hepatitis c virus inhibitors

ABSTRACT

The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, esters, or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     which inhibit RNA-containing virus, particularly the hepatitis C virus (HCV). Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/372,999 filed on Aug. 12, 2010. The entire teachings of the aboveapplication are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to novel antiviral agents. Morespecifically, the present invention relates to compounds which caninhibit the function of the NS5A protein encoded by Hepatitis C Virus(HCV), compositions comprising such compounds, methods for inhibitingHCV viral replication, methods for treating or preventing HCV infection,and processes for making the compounds.

BACKGROUND OF THE INVENTION

Infection with HCV is a major cause of human liver disease throughoutthe world. In the U.S., an estimated 4.5 million Americans arechronically infected with HCV. Although only 30% of acute infections aresymptomatic, greater than 85% of infected individuals develop chronic,persistent infection. Treatment costs for HCV infection have beenestimated at $5.46 billion for the US in 1997. Worldwide over 200million people are estimated to be infected chronically. HCV infectionis responsible for 40-60% of all chronic liver disease and 30% of allliver transplants. Chronic HCV infection accounts for 30% of allcirrhosis, end-stage liver disease, and liver cancer in the U.S. TheCenters for Disease Control and Prevention (CDC) estimates that thenumber of deaths due to HCV will minimally increase to 38,000 per yearby the year 2010.

Due to the high degree of variability in the viral surface antigens,existence of multiple viral genotypes, and demonstrated specificity ofimmunity, the development of a successful vaccine in the near future isunlikely. Alpha-interferon (alone or in combination with ribavirin) hasbeen widely used since its approval for treatment of chronic HCVinfection. However, adverse side effects are commonly associated withthis treatment: flu-like symptoms, leukopenia, thrombocytopenia,depression from interferon, as well as anemia induced by ribavirin(Lindsay, K. L. (1997) Hepatology 26 (suppl 1): 71S-77S). This therapyremains less effective against infections caused by HCV genotype 1(which constitutes ˜75% of all HCV infections in the developed markets)compared to infections caused by the other 5 major HCV genotypes.Unfortunately, only ˜50-80% of the patients respond to this treatment(measured by a reduction in serum HCV RNA levels and normalization ofliver enzymes) and, of responders, 50-70% relapse within 6 months ofcessation of treatment. Recently, with the introduction of pegylatedinterferon (Peg-IFN), both initial and sustained response rates haveimproved substantially, and combination treatment of Peg-IFN withribavirin constitutes the gold standard for therapy. However, the sideeffects associated with combination therapy and the impaired response inpatients with genotype 1 present opportunities for improvement in themanagement of this disease.

First identified by molecular cloning in 1989 (Choo, Q-L et al (1989)Science 244:359-362), HCV is now widely accepted as the most commoncausative agent of post-transfusion non-A, non-B hepatitis (NANBH) (Kuo,G et al (1989) Science 244:362-364). Due to its genome structure andsequence homology, this virus was assigned as a new genus in theFlaviviridae family. Like the other members of the Flaviviridae, such asflaviviruses (e.g. yellow fever virus and Dengue virus types 1-4) andpestiviruses (e.g. bovine viral diarrhea virus, border disease virus,and classic swine fever virus) (Choo, Q-L et al (1989) Science244:359-362; Miller, R. H. and R. H. Purcell (1990) Proc. Natl. Acad.Sci. USA 87:2057-2061), HCV is an enveloped virus containing a singlestrand RNA molecule of positive polarity. The HCV genome isapproximately 9.6 kilobases (kb) with a long, highly conserved,noncapped 5′ nontranslated region (NTR) of approximately 340 bases whichfunctions as an internal ribosome entry site (IRES) (Wang C Y et al ‘AnRNA pseudoknot is an essential structural element of the internalribosome entry site located within the hepatitis C virus 5′ noncodingregion’ RNA—A Publication of the RNA Society. 1(5): 526-537, 1995 Jul.).This element is followed by a region which encodes a single long openreading frame (ORF) encoding a polypeptide of ˜3000 amino acidscomprising both the structural and nonstructural viral proteins.

Upon entry into the cytoplasm of the cell, this RNA is directlytranslated into a polypeptide of ˜3000 amino acids comprising both thestructural and nonstructural viral proteins. This large polypeptide issubsequently processed into the individual structural and nonstructuralproteins by a combination of host and virally-encoded proteinases (Rice,C. M. (1996) in B. N. Fields, D. M. Knipe and P. M. Howley (eds)Virology 2^(nd) Edition, p931-960; Raven Press, N.Y.). There are threestructural proteins, C, E1 and E2. The P7 protein is of unknown functionand is comprised of a highly variable sequence. There are severalnon-structural proteins. NS2 is a zinc-dependent metalloproteinase thatfunctions in conjunction with a portion of the NS3 protein. NS3incorporates two catalytic functions (separate from its association withNS2): a serine protease at the N-terminal end, which requires NS4A as acofactor, and an ATP-ase-dependent helicase function at the carboxylterminus. NS4A is a tightly associated but non-covalent cofactor of theserine protease. NS5A is a membrane-anchored phosphoprotein that isobserved in basally phosphorylated (56 kDa) and hyperphosphorylated (58kDa) forms. While its function has not fully been elucidated, NS5A isbelieved to be important in viral replication. The NS5B protein (591amino acids, 65 kDa) of HCV (Behrens, S. E. et al (1996) EMBO J. 1512-22), encodes an RNA-dependent RNA polymerase (RdRp) activity andcontains canonical motifs present in other RNA viral polymerases. TheNS5B protein is fairly well conserved both intra-typically (˜95-98%amino acid (aa) identity across 1b isolates) and inter-typically (˜85%aa identity between genotype 1a and 1b isolates). The essentiality ofthe HCV NS5B RdRp activity for the generation of infectious progenyvirions has been formally proven in chimpanzees (A. A. Kolykhalov etal., (2000) Journal of Virology, 74(4): 2046-2051). Thus, inhibition ofNS5B RdRp activity (inhibition of RNA replication) is predicted to beuseful to treat HCV infection.

Following the termination codon at the end of the long ORF, there is a3′ NTR which roughly consists of three regions: an ˜40 base region whichis poorly conserved among various genotypes, a variable lengthpoly(U)/polypyrimidine tract, and a highly conserved 98 base elementalso called the “3′ X-tail” (Kolykhalov, A. et al (1996) J. Virology70:3363-3371; Tanaka, T. et al (1995) Biochem Biophys. Res. Commun.215744-749; Tanaka, T. et al (1996) J. Virology 70:3307-3312; Yamada, N.et al (1996) Virology 223:255-261). The 3′ NTR is predicted to form astable secondary structure which is essential for HCV growth in chimpsand is believed to function in the initiation and regulation of viralRNA replication. Compounds useful for treating HCV-infected patients aredesired which selectively inhibit HCV viral replication. In particular,compounds which are effective to inhibit the function of the NS5Aprotein are desired. The HCV NS5A protein is described, for example, inTan, S.-L., Katzel, M. G. Virology 2001, 284, 1; and in Rice, C. M.Nature 2005, 435, 374.

Based on the foregoing, there exists a significant need to identifycompounds with the ability to inhibit HCV.

SUMMARY OF THE INVENTION

The present invention relates to novel antiviral compounds representedherein below, pharmaceutical compositions comprising such compounds, andmethods for the treatment or prophylaxis of viral (particularly HCV)infection in a subject in need of such therapy with said compounds.Compounds of the present invention interfere with the life cycle of thehepatitis C virus and are also useful as antiviral agents.

In its principal aspect, the present invention provides a compound ofFormula (I)

or a pharmaceutically acceptable salt thereof, wherein:

A is absent or a monocyclic or polycyclic group independently selectedfrom the group consisting of aryl, heteroaryl, heterocyclic, C₃-C₈cycloalkyl, and C₃-C₈ cycloalkenyl, each optionally substituted;preferably, A is optionally substituted aryl or optionally substitutedheteroaryl;

B is absent or a monocyclic or polycyclic group independently selectedfrom the group consisting of aryl, heteroaryl, heterocyclic, C₃-C₈cycloalkyl, and C₃-C₈ cycloalkenyl, each optionally substituted;preferably, B is optionally substituted aryl or optionally substitutedheteroaryl;

L is absent or an aliphatic group; when present, L is preferablyselected from the group consisting of O, NH, C(O), C(O)NH, C₁-C₄ alkyl,C₂-C₄ alkenyl, and C₂-C₄ alkynyl, (C₁-C₄ alkyl)-NH—(C₁-C₄ alkyl), andheterocyclic, each optionally substituted;

wherein at least one of A, B and L is present;

W is —C(O)NH— or an optionally substituted 5-membered heteroarylcontaining one or more nitrogen or an optionally substituted5/6-membered fused heteroaryl, wherein the 5-membered ring of said5/6-membered fused heteroaryl contains one or more nitrogen atoms and isattached to the carbon atom to which R^(3a) is also attached, andwherein the 6-membered ring of said 5/6-membered fused heteroaryl isattached to one of groups B, L, and A and is aryl or heteroaryl;preferably, W is an optionally substituted 5-membered heteroarylcontaining one or more nitrogen or optionally substituted 5/6-memberedfused heteroaryl, wherein the 5-membered ring of said 5/6-membered fusedheteroaryl contains one or more nitrogen atoms and is attached to thecarbon atom to which R^(3a) is also attached, and wherein the 6-memberedring of said 5/6-membered fused heteroaryl is attached to one of groupsB, L, and A and is aryl or heteroaryl; more preferably W is anoptionally substituted imidazolyl, optionally substituted benzimidazolylor optionally substituted imidazopyridyl;

Alternatively groups W and B are taken together to form a fusedtricyclic system;

G is absent, —C(O)NH—, an optionally substituted 5-membered heteroarylcontaining one or more nitrogen atoms, or an optionally substituted5/6-membered fused heteroaryl, wherein the 5-membered ring of said5/6-membered fused heteroaryl contains one or more nitrogen atoms and isattached to group Q, and wherein the 6-membered ring of said5/6-membered fused heteroaryl is attached to one of groups A, L and Band is aryl or heteroaryl; preferably, G is an optionally substituted5-membered heteroaryl containing one or more nitrogen atoms or anoptionally substituted 5/6-membered fused heteroaryl, wherein the5-membered ring of said 5/6-membered fused heteroaryl contains one ormore nitrogen atoms and is attached to group Q, and wherein the6-membered ring of said 5/6-membered fused heteroaryl is attached to oneof groups A, L and B and is aryl or heteroaryl; more preferably, G isoptionally substituted imidazolyl, optionally substituted benzimidazolylor optionally substituted imidazopyridyl;

Alternatively groups G and A are taken together to form a fusedtricyclic system;

Q is hydrogen,

Alternatively, G and Q are taken together to form a group selected from:

D is independently a monocyclic or polycyclic group independentlyselected from the group consisting of aryl, heteroaryl, heterocyclic,C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkenyl, each optionally substituted;preferably, B is optionally substituted aryl or optionally substitutedheteroaryl;

E is independently an optionally substituted 5-membered heteroarylcontaining one or more nitrogen atom; preferably, E is an optionallysubstituted imidazolyl;

X¹ at each occurrence is independently N or C(R¹¹); preferably, X¹ is N;

X² at each occurrence is independently N(R¹), O or S; preferably, X² isNH;

X³ and X⁴ are each independently selected from N or C(R¹²); preferably,X³ and X⁴ are each independently CH;

R¹ at each occurrence is independently hydrogen, hydroxy, O(C₁-C₄ alkyl)or optionally substituted C₁-C₄ alkyl;

R¹¹ at each occurrence is independently hydrogen, halogen or optionallysubstituted C₁-C₄ alkyl;

R¹² at each occurrence is independently hydrogen, halogen, hydroxy,optionally substituted C₁-C₄ alkyl, or optionally substituted O(C₁-C₄alkyl);

L¹ and L³ are each independently absent or an aliphatic group, whereinat least one of L¹ and L³ is present; when present, preferably, L¹ andL³ at each occurrence are each independently a linear aliphatic group;

L⁴ and L⁶ are each independently absent or an aliphatic group, whereinat least one of L⁴ and L⁶ is present; when present preferably, L⁴ and L⁶at each occurrence are each independently a linear aliphatic group;

L⁷ and L⁹ at each occurrence are each independently absent or analiphatic group, wherein at least one of L⁷ and L⁹ is present; whenpresent, preferably, L⁷ and L⁹ at each occurrence are each independentlya linear aliphatic group;

L², L⁵, and L⁸ at each occurrence are each independently absent, orselected from the group consisting of aryl, heteroaryl, heterocyclic,C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkenyl, each optionally substituted;

wherein -L¹-L²-L³- together forms a linker; preferably, -L¹-L²-L³-together forms a linker of from 6 to 16 bond lengths;

wherein -L⁴-L⁵-L⁶- together forms a linker; preferably, -L⁴-L⁵-L⁶-together forms a linker of from 8 to 18 bond lengths;

wherein -L⁷-L⁸-L⁹-R⁶— together forms a linker; preferably, -L⁷-L⁸-L⁹-R⁶—together forms a linker of from 8 to 18 bond lengths;

Y at each occurrence is independently C(O) or S(O)₂; preferably, Y isC(O);

R^(3a), R³ and R⁴ at each occurrence are each independently selectedfrom the group consisting of hydrogen, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈ alkenyl, and optionally substitutedC₃-C₈ cycloalkyl; preferably hydrogen or optionally substituted C₁-C₄alkyl; alternatively, R^(3a) and L⁷ or R³ and R⁴ are taken together withthe carbon atom to which they are attached to form optionallysubstituted C₃-C₈ cycloalkyl or optionally substituted heterocyclic;

R⁵ at each occurrence is independently hydrogen, optionally substitutedC₁-C₈ alkyl, or optionally substituted C₃-C₈ cycloalkyl; preferablyhydrogen or optionally substituted C₁-C₄ alkyl;

Alternatively R³, R⁴ and R⁵ are taken together with the carbon andnitrogen atom to which they are attached to form

U is absent or selected from the group consisting of O, S, S(O), SO₂,NC(O)—(C₁-C₄ alkyl), C(O), protected carbonyl, OCH₂, OCH₂CH₂, SCH₂,SCH₂CH₂, C(R⁷)₂, C(R⁷)₂C(R⁷)₂, and C═C(R²)₂; preferably, U is CH₂,C═N-OMe, or C═CH₂;

R² at each occurrence is independently hydrogen, halogen, optionallysubstituted C₁-C₄ alkyl, optionally substituted aryl, or optionallysubstituted heteroaryl;

R⁷ at each occurrence is independently selected from the groupconsisting of hydrogen, halogen, cyano, hydroxy, optionally substitutedO(C₁-C₄ alkyl), S(C₁-C₄ alkyl), amino optionally substituted with one ortwo C₁-C₄ alkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted C₁-C₄ alkyl, and optionallysubstituted C₃-C₈ cycloalkyl; preferably, R⁷ is hydrogen, halogen,methyl, or cyclopropyl;

Alternatively two geminal R⁷ groups are taken together with the carbonatom to which they are attached to form a spiro, optionally substituted3- to 7-membered cyclic group selected from the group consisting ofC₃-C₇ cycloalkyl, C₃-C₇ cycloalkenyl or 3- to 7-membered heterocyclic;preferably, two geminal R⁷ groups are taken together with the carbonatom to which they are attached to form a spiro, optionally substitutedcyclopropyl;

R^(7a) and R^(7b) at each occurrence are each independently selectedfrom the group consisting of hydrogen, optionally substituted aryl,optionally substituted C₁-C₄ alkyl, and optionally substituted C₃-C₈cycloalkyl; preferably, R^(7a) and R^(7b) at each occurrence are eachindependently hydrogen, cyclopropyl or methyl;

Alternatively, CHR^(7a)—U or CHR^(7b)—U are taken together to form agroup selected from CH═CH, fused and optionally substituted C₃-C₈cycloalkyl, fused and optionally substituted aryl, or fused andoptionally substituted heterocyclic; preferably, CHR^(7a)—U orCHR^(7b)—U are taken together to form a fused and optionally substitutedcyclopropyl;

Yet alternatively, U, R^(7a), and R^(7b) are taken together with thecarbon atoms to which they are attached to form a bridged, optionallysubstituted 4- to 7-membered cyclic group selected from the groupconsisting of C₄-C₇ cycloalkyl, C₄-C₇ cycloalkenyl and 4- to 7-memberedheterocyclic; preferably, U, R^(7a), and R^(7b) are taken together withthe carbon atoms to which they are attached to form a bridgedcyclopentyl; and

R⁶ at each occurrence is independently selected from the groupconsisting of O(C₁-C₈ alkyl), amino, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, heterocyclic, aryl, andheteroaryl, each optionally substituted; preferably, R⁶ at eachoccurrence is independently optionally substituted C₁-C₈ alkyl; morepreferably, R⁶ at each occurrence is independently C₁-C₈ alkyloptionally substituted with amino, halogen, hydroxy, aryl, heterocyclic,protected amino or optionally substituted O(C₁-C₄ alkyl).

Each preferred group stated above can be taken in combination with one,any or all other preferred groups.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundor combination of compounds of the present invention, or apharmaceutically acceptable salt thereof, in combination with apharmaceutically acceptable carrier or excipient.

In yet another aspect, the present invention provides a method ofinhibiting the replication of a RNA-containing virus comprisingcontacting said virus with a therapeutically effective amount of acompound or a combination of compounds of the present invention, or apharmaceutically acceptable salt thereof. Particularly, this inventionis directed to methods of inhibiting the replication of HCV.

In still another aspect, the present invention provides a method oftreating or preventing infection caused by an RNA-containing viruscomprising administering to a patient in need of such treatment atherapeutically effective amount of a compound or combination ofcompounds of the present invention, or a pharmaceutically acceptablesalt thereof. Particularly, this invention is directed to methods oftreating or preventing infection caused by HCV.

Yet another aspect of the present invention provides the use of acompound or combination of compounds of the present invention, or atherapeutically acceptable salt thereof, as defined hereinafter, in thepreparation of a medicament for the treatment or prevention of infectioncaused by RNA-containing virus, specifically HCV.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of Formula (I) as illustratedabove, or a pharmaceutically acceptable salt thereof.

The compounds of the invention have utility in inhibiting thereplication of RNA-containing virus, including, for example, HCV. Othercompounds useful for inhibiting the replication of RNA-containingviruses and/or for the treatment or prophylaxis of HCV infection havebeen described in copending U.S. application Ser. No. 12/702,673 filedFeb. 9, 2010 entitled “Linked Dibenzimidazole Antivirals”; U.S.Application Serial No. 12/702,692 filed Feb. 9, 2010 entitled “LinkedDibenzimidazole Derivatives”; U.S. application Ser. No. 12/702,802 filedFeb. 9, 2010 entitled “Linked Dibenzimidazole Derivatives”; U.S.application Ser. No. 12/707,190 filed Feb. 17, 2010 entitled “LinkedDiimidazole Antivirals”; U.S. application Ser. No. 12/707,200 filed Feb.17, 2010 entitled “Linked Diimidazole Derivatives”; U.S. applicationSer. No. 12/707,210 filed Feb. 17, 2010 entitled “Hepatitis C VirusInhibitors”; U.S. application Ser. No. 12/714,583 filed Mar. 1, 2010entitled “Novel Benzimidazole Derivatives”; U.S. application Ser. No.12/714,576 filed Mar. 1, 2010 entitled “Hepatitis C Virus Inhibitors”;U.S. application Ser. No. 12/816,148 filed Jun. 15, 2010 entitled“Hepatitis C Virus Inhibitors”; U.S. application Ser. No. 12/816,171filed Jun. 15, 2010 entitled “Hepatitis C Virus Inhibitors”; U.S.application Ser. No. 12/879,025 filed Sep. 10, 2010 entitled “HepatitisC Virus Inhibitors”; U.S. application Ser. No. 12/879,026 filed Sep. 10,2010 entitled “Hepatitis C Virus Inhibitors”; U.S. application Ser. No.12/879,027 filed Sep. 10, 2010 entitled “Hepatitis C Virus Inhibitors”;U.S. application Ser. No. 12/879,028 filed Sep. 10, 2010 entitled“Hepatitis C Virus Inhibitors”; U.S. application Ser. No. 12/879,029filed Sep. 10, 2010 entitled “Hepatitis C Virus Inhibitors”; U.S.application Ser. No. 12/879,031 filed Sep. 10, 2010 entitled “HepatitisC Virus Inhibitors”; U.S. application Ser. No. 12/851,350 filed Aug. 5,2010 entitled “Combination Pharmaceutical Agents As Inhibitors Of HCVReplication”; U.S. application Ser. No. 12/967,486 filed Dec. 14, 2010entitled “Hepatitis C Virus Inhibitors”; U.S. Application Serial No.13/013,212 filed Jan. 25, 2011 entitled “Hepatitis C Virus Inhibitors”;U.S. Application Serial No. 13/082,621 filed Apr. 8, 2011 entitled“Hepatitis C Virus Inhibitors” and U.S. Application Serial No.13/152,377 filed Jun. 3, 2011 entitled “Hepatitis C Virus Inhibitors;”and the contents of each of which are expressly incorporated byreference herein.

As discussed above, a general strategy for the development of antiviralagents is to inactivate virally encoded proteins, including NS5A, thatare essential for the replication of the virus. The relevant patentdisclosures describing the synthesis of HCV NS5A inhibitors are: US2009/0202478; US 2009/0202483; US 2010/0233120; US 2010/0260708; WO2004/014852; WO 2006/079833; WO 2006/133326; WO 2007/031791; WO2007/070556; WO 2007/070600; WO 2007/082554; WO 2008/021927; WO2008/021928; WO 2008/021936; WO 2008/048589; WO 2008/064218; WO2008/070447; WO 2008/144380; WO 2008/154601; WO 2009/020825; WO2009/020828; WO 2009/034390; WO 2009/102318; WO 2009/102325; WO2009/102694; WO 2010/017401; WO 2010/039793; WO 2010/065668; WO2010/065674; WO 2010/065681; WO 2010/091413; WO 2010/096777; WO2010/096462; WO 2010/096302; WO2010/099527; WO 2010/111483; WO2010/111534; WO 2010/117635; WO 2010/111673; WO 2010/117704; WO2010/132538; WO 2010/132601; WO 2010/138488; WO 2010/138368; WO2010/138790; WO 2010/138791; WO 2010/148006; US 2010/0215618; WO2011/004276; WO 2011/009084; WO 2011/015657; WO 2011/015658; WO2011/026920; WO 2011/028596; WO 2011/031904; WO 2011/031934; WO2011/046811; WO 2011/050146 and WO 2011/054834, WO2011/05988,WO2011/060000, WO2011/066241, WO201/1075439, WO2011/075615,WO2011/079327, WO2011/082077, WO2011/087740, WO2011/091446, the contentsof each of which are expressly incorporated by reference herein.

In one embodiment, the present invention relates to compounds of Formula(I), or pharmaceutically acceptable salts thereof, wherein L is absentor selected from the group consisting of optionally substituted C₁-C₄alkyl, optionally substituted C₂-C₄ alkenyl, and optionally substitutedC₂-C₄ alkynyl.

In some embodiments, the present invention relates to compoundsrepresented by Formula (Ia), (Ib), or (Ic), or pharmaceuticallyacceptable salts thereof:

wherein X¹ is N or C(R¹¹), X² is N(R¹); A, B, G, L, Q, Y, L⁷, L⁸, L⁹,X³, X⁴, R¹, R^(3a), R⁵, R⁶, and R¹¹ are as previously defined.

In one embodiment, the present invention relates to compounds of Formula(Ia), (Ib), or (Ic) or pharmaceutically acceptable salts thereof,wherein L is absent or selected from the group consisting of optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, andoptionally substituted C₂-C₄ alkynyl.

In another embodiment, the present invention relates to compounds ofFormula (Ia), or pharmaceutically acceptable salts thereof; wherein X¹is N and X² is NH.

In another embodiment, the present invention relates to compounds ofFormula (Ib) or (Ic), or pharmaceutically acceptable salts thereof;wherein X¹ is N, X² is NH, X³ and X⁴ are CH.

In another embodiment, the present invention relates to compounds ofFormula (Ia), or pharmaceutically acceptable salts thereof; wherein X¹is N and X² is O or S.

In yet another embodiment, the present invention relates to compounds ofFormula (Ib) or (Ic), or pharmaceutically acceptable salts thereof;wherein X¹ is N, X² is O or S, X³ and X⁴ are CH.

In a further embodiment, the present invention relates to compounds ofFormula (Ib) or (Ic), or pharmaceutically acceptable salts thereof;wherein X¹ is N, X² is NH, X³ is N, and X⁴ is N or CH.

In additional embodiment, the present invention relates to compounds ofFormula (Ib) or (Ic), or pharmaceutically acceptable salts thereof;wherein X¹ is N, X² is NH, X³ is CH, and X⁴ is N.

In another embodiment, the present invention relates to compounds ofFormula (Ia), (Ib) or (Ic), or pharmaceutically acceptable saltsthereof; wherein L⁷ and L⁹ at each occurrence are each independentlyabsent or a linear aliphatic group, wherein at least one of L⁷ and L⁹ ispresent.

In yet another embodiment, the present invention relates to compounds ofFormula (Ia), (Ib) or (Ic), or pharmaceutically acceptable saltsthereof; wherein one of L⁷ and L⁹ is a linear aliphatic group and theother of L⁷ and L⁹ is an aliphatic group containing an optionallysubstituted cycloalkyl, heterocyclic or cycloalkenyl.

In a further embodiment, the present invention relates to compounds ofFormula (Ia), (Ib) or (Ic), or pharmaceutically acceptable saltsthereof; wherein -L⁷-L⁸-L⁹-R⁶— are taken together to form a linker offrom 8 to 18 bond lengths and wherein said linker is a linear aliphaticgroup.

In another embodiment, the present invention relates to compounds ofFormula (Ia), (Ib) or (Ic), or pharmaceutically acceptable saltsthereof; wherein -L⁷-L⁸-L⁹- R⁶— are taken together to form a linker offrom 8 to 18 bond lengths and wherein said linker comprises combinationof one or more linear aliphatic group(s) and a cyclic group.

In yet another aspect of the invention, -L⁷-L⁸-L⁹- R⁶— are takentogether to form a linker of from 8 to 16 bond lengths.

In yet another embodiment, the present invention relates to compoundsrepresented by Formula (Ia-1) or (Ib-1), or pharmaceutically acceptablesalts thereof:

In an additional aspect, the compound has the Formula (Ia-1) or (Ib-1),or is a pharmaceutically acceptable salt thereof wherein A and B at eachoccurrence are each independently absent, optionally substituted aryl,or optionally substituted heteroaryl; L is absent or selected from thegroup consisting of O, —NH—, —C(O)—, —C(O)NH—, C₁-C₄ alkyl, C₂-C₄alkenyl, and C₂-C₄ alkynyl, —(C₁-C₄ alkyl)-NH—(C₁-C₄ alkyl)- andheterocyclic, each optionally substituted; at least one of A, B and L ispresent; L⁷ and L⁹ is each independently a linear aliphatic group; andone of L⁷ and L⁹ is optionally absent; R⁵ is hydrogen or optionallysubstituted C₁-C₄ alkyl; R⁶ at each occurrence is independently C₁-C₈alkyl optionally substituted with amino, halogen, hydroxy, protectedamino or optionally substituted O(C₁-C₄ alkyl); and G is absent, orselected from —C(O)NH—,

and

wherein each of said imidazolyl, benzimidazolyl or imidazopyridyl groupsare each optionally substituted.

In still another embodiment, the present invention relates to compoundsof Formula (I), (Ia), (Ib), (Ic), (Ia-1) or (Ib-1), or pharmaceuticallyacceptable salts thereof; wherein -L⁷-L⁸-L⁹-R⁶— together forms a linkerillustrated by one of the following groups:

wherein R^(x) is hydrogen, amino, hydroxy, protected amino or O(C₁-C₄alkyl); R^(Y) is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, heterocyclic, aryl, or heteroaryl,each optionally substituted; preferably optionally substituted C₁-C₈alkyl; and wherein each of the above shown groups is further optionallysubstituted.

In yet another embodiment, the present invention relates to compounds ofFormula (Id), (Ie) or (If), or pharmaceutically acceptable saltsthereof:

wherein A, B, L, W, Y, L⁷, L⁸, L⁹, R³, R^(3a), R⁴, R⁵, and R⁶ are aspreviously defined; G in Formula (Id) is present and as previouslydefined; in Formulae (Id) and (If), Q is hydrogen.

In another embodiment, the present invention relates to compounds ofFormula (If), or pharmaceutically acceptable salts thereof; wherein oneof A, B and L is absent, and the other two of A, B and L are present andas previously defined.

In yet another embodiment, the present invention relates to compounds ofFormula (If), or pharmaceutically acceptable salts thereof; wherein twoof A, B and L are absent, and the other one of A, B and L is present andas previously defined.

In a further embodiment, the present invention relates to compounds ofFormula (If), or pharmaceutically acceptable salts thereof; wherein eachof A, B and L are present and as previously defined.

In still another embodiment, the present invention relates to compoundsof Formula (I), or pharmaceutically acceptable salts thereof; wherein Gis an optionally substituted five-membered heteroaryl containing one ormore nitrogen atoms, and is C-attached to Q and to one of groups A, Land B.

In still another embodiment, the present invention relates to compoundsof Formula (I), or pharmaceutically acceptable salts thereof; wherein Gis optionally substituted 5/6-membered ring fused heteroaryl, whereinthe 5-membered ring of said 5/6-membered fused heteroaryl is aheteroaryl containing one or more nitrogen atoms and wherein the5-membered ring is C-attached to Q, and wherein the 6-membered ring ofsaid 5/6-membered fused heteroaryl is aryl or heteroaryl and isC-attached to one of groups A, L and B.

In still another embodiment, the present invention relates to compoundsof Formula (I), or pharmaceutically acceptable salts thereof; wherein Gand W are each independently C(O)NH or illustrated by one of thefollowing heteroaryl groups:

wherein each of the above shown heteroaryl groups is optionallysubstituted.

In still another embodiment, the present invention relates to compoundsof Formula (I), or pharmaceutically acceptable salts thereof; wherein Gis optionally substituted imidazolyl, benzimidazolyl or imidazopyridyl.

In still another embodiment, the present invention relates to compoundsof Formula (I), or pharmaceutically acceptable salts thereof; whereingroups G and W are each independently imidazolyl, benzimidazolyl orimidazopyridyl, optionally substituted with halogen, CN, hydroxy,protected hydroxy, amino, protected amino, optionally substituted C₁-C₄alkyl, optionally substituted C₂-C₄ alkenyl, optionally substitutedC₂-C₄ alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted aryl or optionally substituted heteroaryl.

In still another embodiment, the present invention relates to compoundsof Formula (I), or pharmaceutically acceptable salts thereof; wherein Lis a linear aliphatic group, and A and B are each independentlyoptionally substituted phenyl, monocyclic heteroaryl, naphthyl, orbicyclic heteroaryl.

In still another embodiment, the present invention relates to compoundsof Formula (I), or pharmaceutically acceptable salts thereof; wherein Lis a linear aliphatic group, and A and B are each independentlyoptionally substituted phenyl.

In still another embodiment, the present invention relates to compoundsof Formula (I), or pharmaceutically acceptable salts thereof; wherein Aand B are each independently optionally substituted phenyl; L is—CH₂N(R)CH₂—, wherein R is optionally substituted aryl or heteroaryl;preferably, A and B are each optionally substituted phenyl.

In still another embodiment, the present invention relates to compoundsof Formula (I), or pharmaceutically acceptable salts thereof; wherein Lis an optionally substituted heterocyclic, and A and B are eachindependently optionally substituted phenyl, optionally substitutedmonocyclic heteroaryl, optionally substituted naphthyl, or optionallysubstituted bicyclic heteroaryl.

In still another embodiment, the present invention relates to compoundsof Formula (I), or pharmaceutically acceptable salts thereof; wherein Aand B are each independently optionally substituted phenyl and L is apyrrolidinyl group substituted with a phenyl or heteroaryl, wherein saidphenyl or heteroaryl may be optionally further substituted.

In still another embodiment, the present invention relates to compoundsof Formula (I), or pharmaceutically acceptable salts thereof; wherein Lis absent, and A and B are each independently phenyl, monocyclicheteroaryl, naphthyl, or bicyclic heteroaryl, each optionallysubstituted.

In still another embodiment, the present invention relates to compoundsof Formula (I), or pharmaceutically acceptable salts thereof; wherein Aand L are each absent, and B is a fused, optionally substitutedpolycyclic aryl or is a fused, optionally substituted heteroaryl.

In still another embodiment, the present invention relates to compoundsof Formula (I), or pharmaceutically acceptable salts thereof; wherein Aand L are each absent, and group B is a fused polycyclic group selectedfrom the following groups:

wherein each of the above shown cyclic groups is optionally substituted.

In still another embodiment, the present invention relates to compoundsof Formula (I), or pharmaceutically acceptable salts thereof; wherein Gand A are taken together to form a fused tricyclic system selected fromthe following groups:

wherein each of the above shown heteroaryl groups is optionallysubstituted.

In still another embodiment, the present invention relates to compoundsof Formula (I), or pharmaceutically acceptable salts thereof; wherein Wand B are taken together to form a fused tricyclic system selected fromthe following groups:

wherein each of the above shown groups is optionally substituted.

In still another embodiment, the present invention relates to compoundsof Formula (I), or pharmaceutically acceptable salts thereof; wherein Lis absent, and A and B are taken together to form a linker selected fromthe following groups:

wherein each of the above shown cyclic groups is optionally substituted.

In still another embodiment, the present invention relates to compoundsof Formula (I), or pharmaceutically acceptable salts thereof; whereingroups A, L and B are taken together to form a linker selected from thefollowing groups:

wherein each of the above shown groups is optionally substituted.

In still another embodiment, the present invention relates to compoundsof Formula (I), or pharmaceutically acceptable salts thereof; wherein Lis optionally substituted C₂-C₄ alkenyl or optionally substituted C₂-C₄alkynyl; and wherein one of A and B is absent, and the other of A and Bis independently optionally substituted phenyl, optionally substitutedmonocyclic heteroaryl, optionally substituted naphthyl, or optionallysubstituted bicyclic heteroaryl.

In still another embodiment, the present invention relates to compoundsof Formulae (II-a˜II-c), or pharmaceutically acceptable salts thereof;

wherein A, B, G, L, U, W, Y, L⁷, L⁸, L⁹, R¹, R³, R^(3a), R⁴, R⁵, R^(7a),and R^(7b) are as previously defined.

In still another embodiment, the present invention relates to compoundsof Formulae (II-a˜II-c), or pharmaceutically acceptable salts thereof;wherein Y is C(O); R⁶ is C₁-C₈ alkyl optionally substituted with amino,halogen, hydroxy, protected amino or optionally substituted O(C₁-C₄alkyl).

In still another embodiment, the present invention relates to compoundsof Formulae (II-d˜II-g), or pharmaceutically acceptable salts thereof;

wherein A, B, D, E, L, U, W, Y, L¹, L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹, X¹,X², X³, X⁴, R¹, R^(3a), R⁵, R⁶, R^(7a), and R^(7b) are as previouslydefined.

In still another embodiment, the present invention relates to compoundsof Formulae (II-d˜II-f), or pharmaceutically acceptable salts thereof;wherein -L¹-L²-L³- together forms a linker illustrated by one of thefollowing groups:

wherein R^(x) and R^(y) are as previously defined.

In still another embodiment, the present invention relates to compoundsof Formula (II-g), or pharmaceutically acceptable salts thereof; wherein-L⁴-L⁵-L⁶- together forms a linker illustrated by one of the followinggroups:

wherein R^(x) and R^(y) are as previously defined.

In still another embodiment, the present invention relates to compoundsof Formulae (IIIa˜IIId), or pharmaceutically acceptable salts thereof;

wherein U, L⁷, L⁸, L⁹, X², X³, X⁴, R⁵, R^(7a), and R^(7b) are aspreviously defined; R⁶ is C₁-C₈ alkyl optionally substituted with amino,halogen, hydroxy, protected amino, or optionally substituted O(C₁-C₄alkyl); A and B are each independently phenyl, monocyclic heteroaryl,bicyclic aryl, or bicyclic heteroaryl, each optionally substituted; L isO, NH, C(O), C(O)NH, C₁-C₄ alkyl, C₂-C₄ alkenyl, and C₂-C₄ alkynyl,(C₁-C₄ alkyl)-NH—(C₁-C₄ alkyl) and heterocyclic, each optionallysubstituted; and -L⁷-L⁸-L⁹-R⁶— together forms a linker of from 8 to 18bond lengths.

In still another embodiment, the present invention relates to compoundsof Formulae (IVa˜IVf), or pharmaceutically acceptable salts thereof;

wherein U, X², X³, X⁴, R⁵, R⁶, R^(7a), and R^(7b) are as previouslydefined; A, B and D are each independently phenyl, monocyclicheteroaryl, bicyclic aryl, or bicyclic heteroaryl, each optionallysubstituted; L is O, NH, C(O), C(O)NH, C₁-C₄ alkyl, C₂-C₄ alkenyl, andC₂-C₄ alkynyl, (C₁-C₄ alkyl)-NH—(C₁-C₄ alkyl), and heterocyclic, eachoptionally substituted; -L¹-L²-L³- together forms a linker of from 6 to16 bond lengths, and each of -L⁴-L⁵-L⁶- and -L⁷-L⁸-L⁹-R⁶— independentlyform linkers of from 8 to 18 bond lengths.

In still another embodiment, the present invention relates to compoundsof Formulae (Va˜Vd), or pharmaceutically acceptable salts thereof;

wherein R⁵ is hydrogen or optionally substituted C₁-C₄ alkyl; R⁶ isC₁-C₈ alkyl optionally substituted with amino, halogen, hydroxy,protected amino, or optionally substituted O(C₁-C₄ alkyl); U is CH₂,CHF, CHMe, CF₂, C═CH₂, C═CF₂, or C(R⁷)₂; R⁷ at each occurrence isindependently selected from the group consisting of hydrogen, halogen,cyano, hydroxy, optionally substituted O(C₁-C₄ alkyl), amino optionallysubstituted with one or two C₁-C₄ alkyl, and optionally substitutedC₁-C₄ alkyl; alternatively two geminal R⁷ groups are taken together withthe carbon to which they are attached to form a spiro, optionallysubstituted 3- to 7-membered cycloalkyl, cycloalkenyl or heterocyclicring; R^(7a) is hydrogen; and R^(7b) is hydrogen or methyl; oralternatively, R^(7a) and U or U and R^(7b) are taken together with thecarbon to which they are attached to form a fused, optionallysubstituted cyclopropyl, and the other of R^(7b) or R^(7a) is hydrogen;or yet alternatively U, R^(7a) and R^(7b) are taken together with thecarbon to which they are attached to form a bridged, optionallysubstituted C₄-C₇ cycloalkyl; -L¹-L²-L³- together form a linker of from6 to 16 bond lengths, and the -L⁴-L⁵-L⁶- and -L⁷-L⁸-L⁹- R⁶— eachindependently form linkers of from 8 to 18 bond lengths.

In still another embodiment, the present invention relates to compoundsof Formulae (Ve˜Vh), or pharmaceutically acceptable salts thereof;

wherein R⁵ is hydrogen or optionally substituted C₁-C₄ alkyl; R⁶ isC₁-C₈ alkyl optionally substituted with amino, halogen, hydroxy,protected amino, or optionally substituted O(C₁-C₄ alkyl); U at eachoccurrence is independently CH₂, CHF, CHMe, CF₂, C═CH₂, C═CF₂, orC(R⁷)₂; R⁷ at each occurrence is independently selected from the groupconsisting of hydrogen, halogen, cyano, hydroxy, optionally substitutedO(C₁-C₄ alkyl), amino optionally substituted with one or two C₁-C₄alkyl, and optionally substituted C₁-C₄ alkyl; alternatively two geminalR⁷ groups are taken together with the carbon to which they are attachedto form a spiro, optionally substituted 3- to 7-membered cycloalkyl,cycloalkenyl or heterocyclic ring; R^(7a) is hydrogen; and R^(7b) ishydrogen or methyl; or alternatively, R^(7a) and U or U and R^(7b) aretaken together with the carbon to which they are attached to form afused, optionally substituted cyclopropyl, and the other of R^(7b) orR^(7a) is hydrogen; or yet alternatively U, R^(7a) and R^(7b) are takentogether with the carbon to which they are attached to form a bridged,optionally substituted C₄-C₇ cycloalkyl; -L¹-L²-L³- together forms alinker of from 6 to 16 bond lengths, and -L⁷-L⁸-L⁹- R⁶— together forms alinker of from 8 to 18 bond lengths. In another aspect, L is optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl; and-L⁷-L⁸-L⁹- R⁶— together forms a linker of from 8 to 16 bond lengths. Inyet another aspect, L is optionally substituted C₂-C₄ alkenyl, oroptionally substituted C₂-C₄ alkynyl; and -L⁷-L⁸-L⁹- R⁶— together formsa linker of from 8 to 14 bond lengths.

In one embodiment, the compounds of the invention include compounds ofFormula (VIa) and (VIb), and pharmaceutically acceptable salts thereof:

wherein Y and R₆ are as defined above in Formula (I). Preferably, Y isC(O) and R₆ is O(C₁-C₈ alkyl), amino, C₁-C₈ alkyl, aryl, heteroaryl,C₃-C₈ cycloalkyl, or heterocyclic, each optionally substituted. In anadditional embodiment, the compound has the Formula (VIa) or (VIb), or apharmaceutically acceptable salt thereof, wherein Y is C(O) and R⁶ isC₁-C₈ alkyl optionally substituted with amino.

In still another embodiment, the present invention relates to compoundsof Formula (I), or pharmaceutically acceptable salts thereof; wherein

at each occurrence is independently illustrated by one of the followinggroups:

wherein each of the above shown groups is optionally substituted.

In yet another embodiment, the invention is directed to a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein:

A is absent or independently a monocyclic or polycyclic groupindependently selected from the group consisting of aryl, heteroaryl,heterocyclic, C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkenyl, each optionallysubstituted; preferably optionally substituted aryl or optionallysubstituted heteroaryl;

B at each occurrence is independently a monocyclic or polycyclic groupindependently selected from the group consisting of aryl, heteroaryl,heterocyclic, C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkenyl, each optionallysubstituted; preferably optionally substituted aryl or optionallysubstituted heteroaryl;

W is an optionally substituted 5-membered heteroaryl containing one ormore nitrogen or optionally substituted 5/6-membered fused heteroaryl,wherein the 5-membered ring of said 5/6-membered fused heteroarylcontains one or more nitrogen and is attached to the carbon atom towhich R^(3a) is also attached, and wherein the 6-membered ring of said5/6-membered fused heteroaryl is attached to group B, L or A and is arylor heteroaryl; preferably optionally substituted imidazolyl, optionallysubstituted benzimidazolyl or optionally substituted imidazopyridyl;

L is absent or selected from the group consisting of O, optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, andoptionally substituted C₂-C₄ alkynyl;

G is absent or an optionally substituted 5-membered heteroarylcontaining one or more nitrogen atoms or optionally substituted5/6-membered fused heteroaryl, wherein the 5-membered ring of said5/6-membered fused heteroaryl contains one or more nitrogen atoms and isattached to group Q, and wherein the 6-membered ring of said5/6-membered fused heteroaryl is attached to one of groups A, L and Band is aryl or heteroaryl; preferably optionally substituted imidazolyl,optionally substituted benzimidazolyl or optionally substitutedimidazopyridyl;

Q is hydrogen,

Alternatively, G and Q can be taken together to form a group selectedfrom:

E is independently an optionally substituted 5-membered heteroarylcontaining one or more nitrogen atom; preferably optionally substitutedimidazolyl;

X¹ at each occurrence is independently N or C(R¹¹); preferably N;

X² at each occurrence is independently N(R¹), O or S; preferably NH;

X³ and X⁴ are each independently selected from N or C(R¹²); preferablyCH;

R¹ at each occurrence is independently hydrogen or optionallysubstituted C₁-C₄ alkyl;

R¹¹ at each occurrence is independently hydrogen, halogen or optionallysubstituted C₁-C₄ alkyl;

R¹² at each occurrence is independently hydrogen, halogen, hydroxy,optionally substituted C₁-C₄ alkyl, or optionally substituted O(C₁-C₄alkyl);

L¹ and L³ at each occurrence are each independently absent or analiphatic group, wherein at least one of L¹ and L³ is present;preferably, a linear aliphatic group;

L⁴ and L⁶ at each occurrence are each independently absent or analiphatic group, wherein at least one of L⁴ and L⁶ is present;preferably, a linear aliphatic group;

L⁷ and L⁹ at each occurrence are each independently absent or analiphatic group, wherein at least one of L⁷ and L⁹ is present;preferably, a linear aliphatic group;

L², L⁵, and L⁸ at each occurrence are each independently absent, orselected from the group consisting of aryl, heteroaryl, heterocyclic,C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkenyl, each optionally substituted;

wherein -L¹-L²-L³- together forms a linker; preferably a linker of from6 to 16 bond lengths;

wherein -L⁴-L⁵-L⁶- together forms a linker; preferably a linker of from8 to 18 bond lengths;

wherein -L⁷-L⁸-L⁹-R⁶— together forms a linker; preferably a linker offrom 8 to 18 bond lengths;

Y at each occurrence is independently C(O) or S(O)₂; preferably C(O);

R^(3a), R³ and R⁴ at each occurrence are each independently selectedfrom the group consisting of hydrogen, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈ alkenyl, and optionally substitutedC₃-C₈ cycloalkyl; preferably hydrogen or optionally substituted C₁-C₄alkyl; alternatively, R^(3a) and L⁷ or R³ and R⁴ are taken together withthe carbon atom to which they are attached to form optionallysubstituted C₃-C₈ cycloalkyl or optionally substituted heterocyclic;

R⁵ at each occurrence is independently hydrogen, optionally substitutedC₁-C₈ alkyl, or optionally substituted C₃-C₈ cycloalkyl; preferablyhydrogen or optionally substituted C₁-C₄ alkyl;

Alternatively R³, R⁴ and R⁵ are taken together with the carbon andnitrogen atom to which they are attached to form

U is absent or independently selected from the group consisting of O, S,S(O), SO₂, NC(O)—(C₁-C₄ alkyl), C(O), protected carbonyl, OCH₂, OCH₂CH₂,SCH₂, SCH₂CH₂, C(R⁷)₂, C(R⁷)₂C(R⁷)₂, and C═C(R²)₂; preferably, CH₂,C═N-OMe, or C═CH₂;

R² at each occurrence is independently hydrogen, halogen, optionallysubstituted C₁-C₄ alkyl, optionally substituted aryl, or optionallysubstituted heteroaryl;

R⁷ at each occurrence is independently selected from the groupconsisting of hydrogen, halogen, cyano, hydroxy, optionally substitutedO(C₁-C₄ alkyl), S(C₁-C₄ alkyl), amino optionally substituted with one ortwo C₁-C₄ alkyl, optionally substituted aryl, optionally substitutedheteroaryl, and optionally substituted C₁-C₄ alkyl; preferably hydrogen,halogen or hydroxy;

Alternatively two geminal R⁷ groups are taken together with the carbonatom to which they are attached to form a spiro, optionally substituted3- to 7-membered cycloalkyl, cycloalkenyl or heterocyclic ring;preferably, spiro cyclopropyl;

R^(7a) and R^(7b) at each occurrence are each independently selectedfrom the group consisting of hydrogen, optionally substituted aryl, andoptionally substituted C₁-C₄ alkyl; preferably hydrogen or methyl;

Alternatively, CHR^(7a)—U or CHR^(7b)—U are taken together to form agroup selected from CH═CH, fused and optionally substituted C₃-C₈cycloalkyl, fused and optionally substituted aryl, or fused andoptionally substituted heterocyclic; preferably, fused and optionallysubstituted cyclopropyl;

Yet alternatively, U, R^(7a), and R^(7b) are taken together with thecarbon atoms to which they are attached to form a bridged, optionallysubstituted 4- to 7-membered ring including cycloalkyl, cycloalkenyl andheterocyclic; preferably bridged cyclopentyl; and

R⁶ at each occurrence is independently selected from the groupconsisting of O(C₁-C₈ alkyl), amino, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, heterocyclic, aryl, andheteroaryl, each optionally substituted; preferably optionallysubstituted C₁-C₈ alkyl; more preferably C₁-C₈ alkyl optionallysubstituted with amino, halogen, hydroxy, protected amino or optionallysubstituted O(C₁-C₄ alkyl).

Representative compounds of the present invention are those selectedfrom compounds 1-354 compiled in Tables 1-12:

TABLE 1 Compounds 1-219.

Entry

 1

 2

 3

 4

 5

 6

 7

 8

 9

 10

 11

 12

 13

 14

 15

 16

 17

 18

 19

 20

 21

 22

 23

 24

 25

 26

 27

 28

 29

 30

 31

 32

 33

 34

 35

 36

 37

 38

 39

 40

 41

 42

 43

 44

 45

 46

 47

 48

 49

 50

 51

 52

 53

 54

 55

 56

 57

 58

 59

 60

 61

 62

 63

 64

 65

 66

 67

 68

 69

 70

 71

 72

 73

 74

 75

 76

 77

 78

 79

 80

 81

 82

 83

 84

 85

 86

 87

 88

 89

 90

 91

 92

 93

 94

 95

 96

 97

 98

 99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

TABLE 2 Compounds 220-229.

Entry R R′ R″ U 220 Me H H CH₂ 221 H H H CF₂ 222 Me H H S 223 H H H

224 H Me H CH₂ 225 H H H

226 H Ph H CH₂ 227 H H H

228 H H Ph CH₂ 229 H H H

TABLE 3 Compounds 230-239.

Entry R R′ R″ 230 Me H H 231 H CO₂Me H 232 H F H 233 H H CO₂Me 234 H H F235 H OMe H 236 H Cl H 237 H H OMe 238 H H Cl 239 H CF₃ H

TABLE 4 Compounds 240-249.

Entry R R′ R″ R′′′ 240 F H H H 241 F F H H 242 Me H H H 243 Me Me H H244 H H Me Me 245 H H Et Et 246 CF₃ H H H 247 CF₃ H CF₃ H 248 Cl H H H249 Cl H Cl H

TABLE 5 Compounds 250-264.

Entry R 250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

TABLE 6 Compounds 265-282.

Entry A^(a) 265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

TABLE 7 Compounds 283-303.

Entry A^(a) 283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

TABLE 8 Compounds 304-315.

Entry G^(g) 304

305

306

307

308

309

310

311

312

313

314

315

TABLE 9 Compounds 316-333.

Entry L^(a)—L^(b)—L^(c)—R^(d) 316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

TABLE 10 Compounds 334-343.

Compound 334

Compound 335

Compound 336

Compound 337

Compound 338

Compound 339

Compound 340

Compound 341

Compound 342

Compound 343

TABLE 11 Compounds 344-346.

Compound 344

Compound 345

Compound 346

TABLE 12 Compounds 347-354.

Compound 347

Compound 348

Compound 349

Compound 350

Compound 351

Compound 352

Compound 353

Compound 354

It will be appreciated that the description of the present inventionherein should be construed in congruity with the laws and principals ofchemical bonding. In some instances it may be necessary to remove ahydrogen atom in order to accommodate a substitutent at any givenlocation.

It is intended that the definition of any substituent or variable (e.g.,R¹, R⁷, Y, etc.) at a particular location in a molecule be independentof its definitions elsewhere in that molecule. For example, when U isC(R⁷)₂, each of the two R⁷ groups may be the same or different.

It will be yet appreciated that the compounds of the present inventionmay contain one or more asymmetric carbon atoms and may exist inracemic, diastereoisomeric, and optically active forms. It will still beappreciated that certain compounds of the present invention may exist indifferent tautomeric forms. All tautomers are contemplated to be withinthe scope of the present invention.

It should be understood that the compounds encompassed by the presentinvention are those that are suitably stable for use as pharmaceuticalagent.

It will be further appreciated that reference herein to therapy and/ortreatment includes, but is not limited to, prevention, retardation,prophylaxis, therapy and/or cure of the disease. It will further beappreciated that references herein to treatment or prophylaxis of HCVinfection includes treatment or prophylaxis of HCV-associated diseasesuch as liver fibrosis, cirrhosis and hepatocellular carcinoma.

A further embodiment of the present invention includes pharmaceuticalcompositions comprising any single compound or a combination of two ormore compounds delineated herein, or a pharmaceutically acceptable saltthereof, with a pharmaceutically acceptable carrier or excipient.

Yet a further embodiment of the present invention is a pharmaceuticalcomposition comprising any single compound or a combination of two ormore compounds delineated herein, or a pharmaceutically acceptable saltthereof, in combination with one or more agents known in the art, with apharmaceutically acceptable carrier or excipient.

It will be further appreciated that compounds of the present inventioncan be administered as the sole active pharmaceutical agent, or used incombination with one or more agents to treat or prevent hepatitis Cinfections or the symptoms associated with HCV infection. Other agentsto be administered in combination with a compound or combination ofcompounds of the present invention include therapies for disease causedby HCV infection that suppresses HCV viral replication by direct orindirect mechanisms. These agents include, but are not limited to, hostimmune modulators (for example, interferon-alpha, pegylatedinterferon-alpha, consensus interferon, interferon-beta,interferon-gamma, CpG oligonucleo-tides and the like); antiviralcompounds that inhibit host cellular functions such as inosinemonophosphate dehydrogenase (for example, ribavirin and the like);cytokines that modulate immune function (for example, interleukin 2,interleukin 6, and interleukin 12); a compound that enhances thedevelopment of type 1 helper T cell response; interfering RNA;anti-sense RNA; vaccines comprising HCV antigens or antigen adjuvantcombinations directed against HCV; agents that interact with hostcellular components to block viral protein synthesis by inhibiting theinternal ribosome entry site (IRES) initiated translation step of HCVviral replication or to block viral particle maturation and release withagents targeted toward the viroporin family of membrane proteins suchas, for example, HCV P7 and the like; and any agent or combination ofagents that inhibit the replication of HCV by targeting other proteinsof the viral genome involved in the viral replication and/or interferewith the function of other viral targets, such as inhibitors of NS3/NS4Aprotease, NS3 helicase, NS5B polymerase, NS4A protein and NS5A protein.

According to yet another embodiment, the pharmaceutical compositions ofthe present invention may further comprise other inhibitor(s) of targetsin the HCV life cycle, including, but not limited to, helicase,polymerase, metalloprotease, NS4A protein, NS5A protein, and internalribosome entry site (IRES).

Accordingly, one embodiment of the present invention is directed to amethod for treating or preventing an infection caused by anRNA-containing virus comprising co-administering to a patient in need ofsuch treatment one or more agents selected from the group consisting ofa host immune modulator and a second or more antiviral agents, or acombination thereof, with a therapeutically effective amount of acompound or combination of compounds of the present invention, or apharmaceutically acceptable salt thereof. Examples of the host immunemodulator include, but are not limited to, interferon-alpha,pegylated-interferon-alpha, interferon-beta, interferon-gamrna, acytokine, a vaccine, and a vaccine comprising an antigen and anadjuvant, and said second antiviral agent inhibits replication of HCVeither by inhibiting host cellular functions associated with viralreplication or by targeting proteins of the viral genome. A non-limitingexample of the RNA-containing virus is hepatitis C virus (HCV).

A further embodiment of the present invention is directed to a method oftreating or preventing infection caused by an RNA-containing viruscomprising co-administering to a patient in need of such treatment anagent or combination of agents that treat or alleviate symptoms of HCVinfection including cirrhosis and inflammation of the liver, with atherapeutically effective amount of a compound or combination ofcompounds of the present invention, or a pharmaceutically acceptablesalt thereof. A non-limiting example of the RNA-containing virus ishepatitis C virus (HCV).

Yet another embodiment of the present invention provides a method oftreating or preventing infection caused by an RNA-containing viruscomprising co-administering to a patient in need of such treatment oneor more agents that treat patients for disease caused by hepatitis B(HBV) infection, with a therapeutically effective amount of a compoundor a combination of compounds of the present invention, or apharmaceutically acceptable salt thereof. An agent that treats patientsfor disease caused by hepatitis B (HBV) infection may be for example,but not limited thereto, L-deoxythymidine, adefovir, lamivudine ortenfovir, or any combination thereof. A non-limiting example of theRNA-containing virus is hepatitis C virus (HCV).

A further embodiment of the present invention provides a method oftreating or preventing infection caused by an RNA-containing viruscomprising co-administering to a patient in need of such treatment oneor more agents that treat patients for disease caused by humanimmunodeficiency virus (HIV) infection, with a therapeutically effectiveamount of a compound or a combination of compounds of the presentinvention, or a pharmaceutically acceptable salt thereof. The agent thattreats patients for disease caused by human immuno-deficiency virus(HIV) infection may include, but is not limited thereto, ritonavir,lopinavir, indinavir, nelfinavir, saquinavir, amprenavir, atazanavir,tipranavir, TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine,stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine,delavirdine, TMC-125, L-870812, S-1360, enfuvirtide (T-20) or T-1249, orany combination thereof. A non-limiting example of the RNA-containingvirus is hepatitis C virus (HCV).

It can occur that a patient may be co-infected with hepatitis C virusand one or more other viruses, including, but not limited to, humanimmunodeficiency virus (HIV), hepatitis A virus (HAV) and hepatitis Bvirus (HBV). Thus, also contemplated herein is combination therapy totreat such co-infections by co-administering a compound according to thepresent invention with at least one of an HIV inhibitor, an HAVinhibitor and an HBV inhibitor.

In addition, the present invention provides the use of a compound or acombination of compounds of the invention, or a therapeuticallyacceptable salt thereof, and one or more agents selected from the groupconsisting of a host immune modulator and one or more additionalantiviral agents, or a combination thereof, to prepare a medicament forthe treatment of an infection caused by an RNA-containing virus in apatient, particularly hepatitis C virus. Non-limiting examples of thehost immune modulators include, but are not limited to,interferon-alpha, pegylated-interferon-alpha, interferon-beta,interferon-gamma, a cytokine, a vaccine, and a vaccine comprising anantigen and an adjuvant. Preferably said additional antiviral agentinhibits replication of HCV either by inhibiting host cellular functionsassociated with viral replication or by targeting proteins of the viralgenome.

When used in the above or other treatments, combination of compound orcompounds of the present invention, together with one or more agents asdefined herein above, can be employed in pure form or, where such formsexist, or as a pharmaceutically acceptable salt thereof. Alternatively,such combination of therapeutic agents can be administered as apharmaceutical composition containing a therapeutically effective amountof the compound or combination of compounds of interest, or theirpharmaceutically acceptable salt thereof, in combination with one ormore agents as defined hereinabove, and a pharmaceutically acceptablecarrier. Such pharmaceutical compositions can be used for inhibiting thereplication of an RNA-containing virus, particularly Hepatitis C virus(HCV), by contacting said virus with said pharmaceutical composition. Inaddition, such compositions are useful for the treatment or preventionof an infection caused by an RNA-containing virus, particularlyHepatitis C virus (HCV).

Hence, a still further embodiment of the invention is directed to amethod of treating or preventing infection caused by an RNA-containingvirus, particularly a hepatitis C virus (HCV), comprising administeringto a patient in need of such treatment a pharmaceutical compositioncomprising a compound or combination of compounds of the invention or apharmaceutically acceptable salt thereof, and one or more agents asdefined hereinabove, with a pharmaceutically acceptable carrier.

When administered as a combination, the therapeutic agents can beformulated as separate compositions which are given at the same time orwithin a predetermined period of time, or the therapeutic agents can begiven as a single unit dosage form.

Antiviral agents contemplated for use in such combination therapyinclude agents (compounds or biologicals) that are effective to inhibitthe formation and/or replication of a virus in a mammal, including, butnot limited to, agents that interfere with either host or viralmechanisms necessary for the formation and/or replication of a virus ina mammal. Such agents can be selected from another anti-HCV agent; anHIV inhibitor; an HAV inhibitor; and an HBV inhibitor.

Other agents that can be administered in combination with a compound ofthe present invention include a cytochrome P450 monooxygenase inhibitor(also referred to herein as a CYP inhibitor), which is expected toinhibit metabolism of the compounds of the invention. Therefore, thecytochrome P450 monooxygenase inhibitor would be in an amount effectiveto inhibit metabolism of the compounds of this invention. Accordingly,the CYP inhibitor is administered in an amount sufficient to improve oneor more pharmacokinetic (PK) features including, but not limited to,plasma concentration, bioavailiablity, area under the plasmaconcentration time curve (AUC), elimination half-life, and systemicclearance, of a compound of the invention when one or more of its PKfeatures of said compound is improved in comparison to that in theabsence of the CYP inhibitor.

In one embodiment, the invention provides methods for improving thepharmaco-kinetics of compounds of the invention. The advantages ofimproving the pharmacokinetics of drugs are recognized in the art (see,for example, U.S. Patent App. Publication Nos. 2004/0091527,2004/0152625 and US 2004/0091527). Accordingly, one embodiment of thisinvention provides a method comprising administering an inhibitor ofCYP3A4 and a compound of the invention. Another embodiment of thisinvention provides a method comprising administering a compound of theinvention and an inhibitor of isozyme 3A4 (“CYP3A4”), isozyme 2C19(“CYP2C19”), isozyme 2D6 (“CYP2D6”), isozyme 1A2 (“CYP1A2”), isozyme 2C9(“CYP2C9”), or isozyme 2E1 (“CYP2E1”). In a preferred embodiment, theCYP inhibitor preferably inhibits CYP3A4. Any CYP inhibitor thatimproves the pharmacokinetics of the relevant compound of the inventionmay be used in a method of this invention. These CYP inhibitors include,but are not limited to, ritonavir (see, for example, WO 94/14436),ketoconazole, troleandomycin, 4-methylpyrazole, cyclosporin,clomethiazole, cimetidine, itraconazole, fluconazole, miconazole,fluvoxamine, fluoxetine, nefazodone, sertraline, indinavir, nelfinavir,amprenavir, fosamprenavir, saquinavir, lopinavir, delavirdine, ditiazem,erythromycin, VX-944, and VX-497. Preferred CYP inhibitors include, forexample, ritonavir, ketoconazole, troleandomycin, 4-methylpyrazole,cyclosporin, and clomethiazole.

It will be understood that the administration of the combination of theinvention by means of a single patient pack, or patient packs of eachformulation, containing within a package insert instructing the patientto the correct use of the invention is a desirable additional feature ofthis invention.

According to a further aspect of the invention is a pack comprising atleast a compound of the invention and a CYP inhibitor and an informationinsert containing directions on the use of the combination of theinvention. In an alternative embodiment of this invention, the packfurther comprises one or more of additional agent as described herein.The additional agent or agents may be provided in the same pack or inseparate packs.

Another aspect of this involves a packaged kit for a patient to use inthe treatment of HCV infection or in the prevention of HCV infection,comprising: a single or a plurality of pharmaceutical formulation ofeach pharmaceutical component; a container housing the pharmaceuticalformulation(s) during storage and prior to administration; andinstructions for carrying out drug administration in a manner effectiveto treat or prevent HCV infection.

Accordingly, this invention provides kits for the simultaneous orsequential administration of a compound of the invention and a CYPinhibitor (and optionally an additional agent) or derivatives thereofare prepared in a conventional manner. Typically, such a kit willcomprise, e.g. a composition of a compound of the invention andoptionally the additional agent (s) in a pharmaceutically acceptablecarrier (and in one or in a plurality of pharmaceutical formulations)and written instructions for the simultaneous or sequentialadministration.

In another embodiment, a packaged kit is provided that contains one ormore dosage forms for self administration; a container means, preferablysealed, for housing the dosage forms during storage and prior to use;and instructions for a patient to carry out drug administration. Theinstructions will typically be written instructions on a package insert,a label, and/or on other components of the kit, and the dosage form orforms are as described herein. Each dosage form may be individuallyhoused, as in a sheet of a metal foil—plastic laminate with each dosageform isolated from the others in individual cells or bubbles, or thedosage forms may be housed in a single container, as in a plasticbottle. The present kits will also typically include means for packagingthe individual kit components, i.e., the dosage forms, the containermeans, and the written instructions for use. Such packaging means maytake the form of a cardboard or paper box, a plastic or foil pouch, etc.

DEFINITIONS

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “aryl,” as used herein, refers to a mono- or polycycliccarbocyclic ring system comprising at least one aromatic ring,including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl,indanyl, and idenyl. A polycyclic aryl is a polycyclic ring system thatcomprises at least one aromatic ring. Polycyclic aryls can comprisefused rings, covalently attached rings or a combination thereof.

The term “heteroaryl,” as used herein, refers to a mono- or polycyclicaromatic radical having one or more ring atom selected from S, O and N;and the remaining ring atoms are carbon, wherein any N or S containedwithin the ring may be optionally oxidized. Heteroaryl includes, but isnot limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzooxazolyl, and quinoxalinyl. A polycyclic heteroaryl can comprisefused rings, covalently attached rings or a combination thereof.

In accordance with the invention, aromatic groups can be substituted orunsubstituted.

The term “bicyclic aryl” or “bicyclic heteroaryl” refers to a ringsystem consisting of two rings wherein at least one ring is aromatic;and the two rings can be fused or covalently attached.

The term “tricyclic aryl” refers to a ring system consisting of threerings wherein at least one ring is aromatic; and the three rings can befused or covalently attached.

The term “tricyclic heteroaryl” refers to a ring system consisting ofthree rings wherein at least one ring is aromatic having one or morering atom selected from S, O and N; and the remaining ring atoms arecarbon, wherein any N or S contained within the ring may be optionallyoxidized; and the three rings can be fused or covalently attached.

The terms “C₁-C₄ alkyl,” “C₁-C₆ alkyl,” “C₁-C₈ alkyl,” “C₂-C₄ alkyl,” or“C₃-C₆ alkyl,” as used herein, refer to saturated, straight- orbranched-chain hydrocarbon radicals containing between one and four, oneand six, one and eight carbon atoms, or the like, respectively. Examplesof C₁-C₈ alkyl radicals include, but are not limited to, methyl, ethyl,propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl andoctyl radicals.

The terms “C₂-C₈ alkenyl,” “C₂-C₄ alkenyl,” “C₃-C₄ alkenyl,” or “C₃-C₆alkenyl,” as used herein, refer to straight- or branched-chainhydrocarbon radicals containing from two to eight, or two to four carbonatoms, or the like, having at least one carbon-carbon double bond by theremoval of a single hydrogen atom. Alkenyl groups include, but are notlimited to, for example, ethenyl, propenyl, butenyl,1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

The terms “C₂-C₈ alkynyl,” “C₂-C₄ alkynyl,” “C₃-C₄ alkynyl,” or “C₃-C₆alkynyl,” as used herein, refer to straight- or branched-chainhydrocarbon radicals containing from two to eight, or two to four carbonatoms, or the like, having at least one carbon-carbon triple bond by theremoval of a single hydrogen atom. Representative alkynyl groupsinclude, but are not limited to, for example, ethynyl, 1-propynyl,1-butynyl, heptynyl, octynyl, and the like.

The term “C₃-C₈ cycloalkyl”, “C₃-C₇ cycloalkyl”, or “C₄-C₇ cycloalkyl,”as used herein, refers to a monocyclic or polycyclic saturatedcarbocyclic ring compound, and the carbon atoms may be optionallyoxo-substituted. Examples of C₃-C₈ cycloalkyl include, but not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl andcyclooctyl; and examples of C₄-C₇ cycloalkyl include, but not limitedto, cyclopentyl, cyclohexyl, bicyclo [2.2.1]heptyl, and the like.

The term “C₃-C₈ cycloalkenyl”, “C₃-C₇ cycloalkenyl”, or “C₄-C₇cycloalkenyl” as used herein, refers to monocyclic or polycycliccarbocyclic ring compound having at least one carbon-carbon double bond,and the carbon atoms may be optionally oxo-substituted. Examples ofC₃-C₈ cycloalkenyl include, but not limited to, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,and the like; and examples of C₄-C₇ cycloalkenyl include, but notlimited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.

It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclic and cycloalkenyl moiety described herein can also be analiphatic group or an alicyclic group.

An “aliphatic” group is a non-aromatic moiety comprised of anycombination of carbon atoms, hydrogen atoms, halogen atoms, oxygen,nitrogen or other atoms, and optionally contains one or more units ofunsaturation, e.g., double and/or triple bonds. Examples of aliphaticgroups are functional groups, such as, O, OH, NH, NH₂, C(O), S(O)₂,C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH₂, S(O)₂NH, S(O)₂NH₂, NHC(O)NH₂,NHC(O)C(O)NH, NHS(O)₂NH, NHS(O)₂NH₂, C(O)NHS(O)₂, C(O)NHS(O)₂NH orC(O)NHS(O)₂NH₂, and the like, groups comprising one or more functionalgroups, non-aromatic hydrocarbons (optionally substituted), and groupswherein one or more carbons of a non-aromatic hydrocarbon (optionallysubstituted) is replaced by a functional group. Carbon atoms of analiphatic group can be optionally oxo-substituted. An aliphatic groupmay be straight chained, branched, cyclic, or a combination thereof andpreferably contains between about 1 and about 24 carbon atoms, moretypically between about 1 and about 12 carbon atoms. In addition toaliphatic hydrocarbon groups, as used herein, aliphatic groups expresslyinclude, for example, alkoxyalkyls, polyalkoxyalkyls, such aspolyalkylene glycols, polyamines, and polyimines, for example. Aliphaticgroups may be optionally substituted. A linear aliphatic group is anon-cyclic aliphatic group. It is to be understood that when analiphatic group or a linear aliphatic group is said to “contain” or“include” or “comprise” one or more specified functional groups, thealiphatic group can be selected from one or more of the specifiedfunctional groups or a combination thereof, or a group wherein one ormore carbons of a non-aromatic hydrocarbon (optionally substituted) isreplaced by a specified functional group. In some examples, the linearaliphatic group can be represented by the formula M-V-M′, where M and M′are each independently absent or an alkyl, alkenyl or alkynyl, eachoptionally substituted, and V is a functional group. In some examples, Vis selected from the group consisting of C(O), S(O)₂, C(O)O, C(O)N(R¹¹),OC(O)O, OC(O)N(R¹¹), S(O)₂N(R¹¹), N(R¹¹)C(O)N(R¹¹),N(R¹¹)C(O)C(O)N(R¹¹), N(R¹¹)S(O)₂N(R¹¹), C(O)N(R¹¹)S(O)₂ orC(O)N(R¹¹)S(O)₂N(R¹¹); wherein R¹¹ is as previously defined. In anotheraspect of the invention, an exemplary linear aliphatic group is analkyl, alkenyl or alkynyl, each optionally substituted, which isinterrupted or terminated by a functional group such as describedherein.

The term “alicyclic,” as used herein, denotes a monovalent group derivedfrom a monocyclic or bicyclic saturated carbocyclic ring compound by theremoval of a single hydrogen atom, and the carbon atoms may beoptionally oxo-substituted. Examples include, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl,and bicyclo[2.2.2]octyl. Such alicyclic groups may be furthersubstituted.

The terms “heterocyclic” or “heterocycloalkyl” can be usedinterchangeably and referred to a non-aromatic ring or a bi- ortri-cyclic group fused system, where (i) each ring system contains atleast one heteroatom independently selected from oxygen, sulfur andnitrogen, (ii) each ring system can be saturated or unsaturated (iii)the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) thenitrogen heteroatom may optionally be quaternized, (v) any of the aboverings may be fused to an aromatic ring, and (vi) the remaining ringatoms are carbon atoms which may be optionally oxo-substituted.Representative heterocycloalkyl groups include, but are not limited to,1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl,pyridazinonyl, and tetrahydrofuryl. Such heterocyclic groups may befurther substituted. Heteroaryl or heterocyclic groups can be C-attachedor N-attached (where possible).

It is understood that any alkyl, alkenyl, alkynyl, alicyclic,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphaticmoiety or the like, described herein can also be a divalent ormultivalent group when used as a linkage to connect two or more groupsor substituents, which can be at the same or different atom(s).

The term “substituted” refers to substitution by independent replacementof one, two, or three or more of the hydrogen atoms with substituentsincluding, but not limited to, —F, —Cl, —Br, —I, —OH, protected hydroxy,—NO₂, —N₃, —CN, —NH₂, protected amino, oxo, thioxo, —NH—C₁-C₁₂-alkyl,—NH—C₂-C₈-alkenyl, —NH—C₂-C₈-alkynyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl,—NH-heteroaryl, —NH-heterocycloalkyl, -dialkylamino, -diarylamino,-diheteroarylamino, —O—C₁-C₁₂-alkyl, —O—C₂-C₈-alkenyl, —O—C₂-C₈-alkynyl,—O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₈-alkenyl, —C(O)—C₂-C₈-alkynyl,—C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₈-alkenyl,—CONH—C₂-C₈-alkynyl, —CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl,—CONH-heteroaryl, —CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl,—OCO₂—C₂-C₈-alkenyl, —OCO₂—C₂-C₈-alkynyl, —OCO₂—C₃-C₁₂-cycloalkyl,—OCO₂-aryl, —OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —CO₂—C₁-C₁₂ alkyl,—CO₂—C₂-C₈ alkenyl, —CO₂—C₂-C₈ alkynyl, CO₂—C₃-C₁₂-cycloalkyl, —CO₂—aryl, CO₂-heteroaryl, CO₂-heterocyloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₈-alkenyl, —OCONH—C₂-C₈-alkynyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH— heterocyclo-alkyl, —NHC(O)H,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₈-alkenyl, —NHC(O)—C₂-C₈-alkynyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocyclo-alkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₈-alkenyl,—NHCO₂—C₂-C₈-alkynyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂— heterocycloalkyl, —NHC(O)NH₂,—NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₈-alkenyl,—NHC(O)NH—C₂-C₈-alkynyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,—NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₈-alkenyl,—NHC(S)NH—C₂-C₈-alkynyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,—NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₈-alkenyl,—NHC(NH)NH—C₂-C₈-alkynyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl, —NHC(NH)NH-aryl,—NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,—NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₈-alkenyl, —NHC(NH)—C₂-C₈-alkynyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₈-alkenyl, —C(NH)NH—C₂-C₈-alkynyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₈-alkenyl,—S(O)—C₂-C₈-alkynyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl, —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₈-alkenyl, —SO₂NH—C₂-C₈-alkynyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH— heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₈-alkenyl, —NHSO₂—C₂-C₈-alkynyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₈-alkenyl, —S—C₂-C₈-alkynyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthio-methyl. It is understood that the aryls, heteroaryls, alkyls,and the like can be further substituted.

The term “halogen,” as used herein, refers to an atom selected fromfluorine, chlorine, bromine and iodine.

The term “hydrogen” includes hydrogen and deuterium. In addition, therecitation of an atom includes other isotopes of that atom so long asthe resulting compound is pharmaceutically acceptable.

As described above, each of -L¹- L²-L³- taken together, -L⁴-L⁵-L⁶- takentogether and -L⁷-L⁸-L⁹- R⁶— taken together is a linker group ofpreferably from 6 to 16, 8 to 18 and 8 to 18 bond lengths, respectively.The preferred range of bond lengths in the linker group -L⁷-L⁸-L⁹-R⁶—(such as 8 to 18 or the like) is inclusive of the bonds between thelinker group and Y and between the linker group and the carbon atom (towhich carbon atom, the linker group, group W and the R^(3a) areattached). Similarly, the preferred range of bond lengths in the linkergroup -L⁴-L⁵-L⁶- (such as 8 to 18, 8 to 14, or the like) is inclusive ofthe bonds between the linker group and Y and between the linker groupand the atom of a ring in group B (to which atom, the linker group isattached). In addition, the preferred range of bond lengths in thelinker group -L¹-L²-L³- (such as 6 to 16 bond lengths) is inclusive ofthe bonds between the linker group and Y and between the linker groupand the carbon of 6-membered or 5-membered ring of group G. It is to beunderstood that when a linker includes a cyclic group, the preferredbond length is the shortest possible distance, as measured in bondlengths. For example, when the linker group -L⁷-L⁸-L⁹-R⁶— includes acyclic group, the number of bond lengths is measured between Y and thecarbon atom to which the linker group, group W and R^(3a) are attached.Similarly, when the linker group -L⁴-L⁵-L⁶- includes a cyclic group, thenumber of bond lengths is measured between Y and the atom of the ring ofgroup D. When the linker group -L¹-L²-L³- includes a cyclic group, thenumber of bond lengths is measured between Y and the carbon of the6-membered or 5-membered ring of group G.

The term “hydroxy activating group”, as used herein, refers to a labilechemical moiety which is known in the art to activate a hydroxyl groupso that it will depart during synthetic procedures such as in asubstitution or an elimination reaction. Examples of hydroxyl activatinggroup include, but not limited to, mesylate, tosylate, triflate,p-nitrobenzoate, phosphonate and the like.

The term “activated hydroxy”, as used herein, refers to a hydroxy groupactivated with a hydroxyl activating group, as defined above, includingmesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, forexample.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxyl groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s), the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theart are described generally in T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons,New York (1999). Examples of hydroxyl protecting groups includebenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxy-carbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl,chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl,methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, allyl,benzyl, triphenyl-methyl (trityl), methoxymethyl, methylthiomethyl,benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl,trimethylsilyl, triisopropylsilyl, and the like.

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups,for example.

The term “hydroxy prodrug group”, as used herein, refers to a promoietygroup which is known in the art to change the physicochemical, and hencethe biological properties of a parent drug in a transient manner bycovering or masking the hydroxy group. After said syntheticprocedure(s), the hydroxy prodrug group as described herein must becapable of reverting back to hydroxy group in vivo. Hydroxy prodruggroups as known in the art are described generally in Kenneth B. Sloan,Prodrugs, Topical and Ocular Drug Delivery, (Drugs and thePharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York(1992).

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the artare described generally in T. H. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York(1999). Examples of amino protecting groups include, but are not limitedto, methoxycarbonyl, t-butoxycarbonyl, 9-fluorenyl-methoxycarbonyl,benzyloxycarbonyl, and the like.

The term “protected amino,” as used herein, refers to an amino groupprotected with an amino protecting group as defined above.

The term “leaving group” means a functional group or atom which can bedisplaced by another functional group or atom in a substitutionreaction, such as a nucleophilic substitution reaction. By way ofexample, representative leaving groups include chloro, bromo and iodogroups; sulfonic ester groups, such as mesylate, tosylate, brosylate,nosylate and the like; and acyloxy groups, such as acetoxy,trifluoroacetoxy and the like.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such compounds are well known to those skilledin the art, and it will be obvious to those skilled in the art thatindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of aprotic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4th ed., edited by John A. Riddick et al., Vol. II, in theTechniques of Chemistry Series, John Wiley & Sons, NY, 1986.

The term “protic solvent’ as used herein, refers to a solvent that tendsto provide protons, such as an alcohol, for example, methanol, ethanol,propanol, isopropanol, butanol, t-butanol, and the like. Such solventsare well known to those skilled in the art, and it will be obvious tothose skilled in the art that individual solvents or mixtures thereofmay be preferred for specific compounds and reaction conditions,depending upon such factors as the solubility of reagents, reactivity ofreagents and preferred temperature ranges, for example. Furtherdiscussions of protogenic solvents may be found in organic chemistrytextbooks or in specialized monographs, for example: Organic SolventsPhysical Properties and Methods of Purification, 4th ed., edited by JohnA. Riddick et al., Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, NY, 1986.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the Formula (I) described herein will be evident to thoseof ordinary skill in the art. Additionally, the various synthetic stepsmay be performed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, 2^(nd) Ed. Wiley-VCH (1999); T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley andSons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The term “subject” as used herein refers to an animal. Preferably, theanimal is a mammal. More preferably, the mammal is a human. A subjectalso refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and may include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers or cis- and trans-isomers. Likewise, alltautomeric forms are also intended to be included. Tautomers may be incyclic or acyclic. The configuration of any carbon-carbon double bondappearing herein is selected for convenience only and is not intended todesignate a particular configuration unless the text so states; thus acarbon-carbon double bond or carbon-heteroatom double bond depictedarbitrarily herein as trans may be cis, trans, or a mixture of the twoin any proportion.

Certain compounds of the present invention may also exist in differentstable conformational forms which may be separable. Torsional asymmetrydue to restricted rotation about an asymmetric single bond, for examplebecause of steric hindrance or ring strain, may permit separation ofdifferent conformers. The present invention includes each conformationalisomer of these compounds and mixtures thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, nontoxic acid addition salts are saltsof an amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, maleic acid, tartaric acid,citric acid, succinic acid or malonic acid or by using other methodsused in the art such as ion exchange. Other pharmaceutically acceptablesalts include, but are not limited to, adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentane-propionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals with undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of thepresent invention. “Prodrug”, as used herein means a compound which isconvertible in vivo by metabolic means (e.g. by hydrolysis) to acompound of the invention. Various forms of prodrugs are known in theart, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs,Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4,Academic Press (1985); Krogsgaard-Larsen, et al. (ed.), “Design andApplication of Prodrugs, Textbook of Drug Design and Development,Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug DeliverReviews, 8:1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel DrugDelivery Systems, American Chemical Society (1975); and Bernard Testa &Joachim Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

The present invention also relates to solvates of the compounds ofFormula (I), for example hydrates.

This invention also encompasses pharmaceutical compositions containing,and methods of treating viral infections through administering,pharmaceutically acceptable prodrugs of compounds of the invention. Forexample, compounds of the invention having free amino, amido, hydroxy orcarboxylic groups can be converted into prodrugs. Prodrugs includecompounds wherein an amino acid residue, or a polypeptide chain of twoor more (e.g., two, three or four) amino acid residues is covalentlyjoined through an amide or ester bond to a free amino, hydroxy orcarboxylic acid group of compounds of the invention. The amino acidresidues include but are not limited to the 20 naturally occurring aminoacids commonly designated by three letter symbols and also includes4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminun hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

For pulmonary delivery, a therapeutic composition of the invention isformulated and administered to the patient in solid or liquidparticulate form by direct administration e.g., inhalation into therespiratory system. Solid or liquid particulate forms of the activecompound prepared for practicing the present invention include particlesof respirable size: that is, particles of a size sufficiently small topass through the mouth and larynx upon inhalation and into the bronchiand alveoli of the lungs. Delivery of aerosolized therapeutics,particularly aerosolized antibiotics, is known in the art (see, forexample U.S. Pat. No. 5,767,068 to VanDevanter et al., U.S. Pat. No.5,508,269 to Smith et al., and WO 98/43650 by Montgomery, all of whichare incorporated herein by reference). A discussion of pulmonarydelivery of antibiotics is also found in U.S. Pat. No. 6,014,969,incorporated herein by reference.

Antiviral Activity

An inhibitory amount or dose of the compounds of the present inventionmay range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively fromabout 1 to about 50 mg/Kg. Inhibitory amounts or doses will also varydepending on route of administration, as well as the possibility ofco-usage with other agents.

According to the methods of treatment of the present invention, viralinfections, conditions are treated or prevented in a patient such as ahuman or another animal by administering to the patient atherapeutically effective amount of a compound of the invention, in suchamounts and for such time as is necessary to achieve the desired result.

By a “therapeutically effective amount” of a compound of the inventionis meant an amount of the compound which confers a therapeutic effect onthe treated subject, at a reasonable benefit/risk ratio applicable toany medical treatment. The therapeutic effect may be objective (i.e.,measurable by some test or marker) or subjective (i.e., subject gives anindication of or feels an effect). An effective amount of the compounddescribed above may range from about 0.1 mg/Kg to about 500 mg/Kg,preferably from about 1 to about 50 mg/Kg. Effective doses will alsovary depending on route of administration, as well as the possibility ofco-usage with other agents. It will be understood, however, that thetotal daily usage of the compounds and compositions of the presentinvention will be decided by the attending physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or contemporaneously with thespecific compound employed; and like factors well known in the medicalarts.

The total daily dose of the compounds of this invention administered toa human or other animal in single or in divided doses can be in amounts,for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1to 25 mg/kg body weight. Single dose compositions may contain suchamounts or submultiples thereof to make up the daily dose. In general,treatment regimens according to the present invention compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

The compounds of the present invention described herein can, forexample, be administered by injection, intravenously, intraarterially,subdermally, intraperitoneally, intramuscularly, or subcutaneously; ororally, buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.1 toabout 500 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect. Typically, the pharmaceutical compositions ofthis invention will be administered from about 1 to about 6 times perday or alternatively, as a continuous infusion. Such administration canbe used as a chronic or acute therapy. The amount of active ingredientthat may be combined with pharmaceutically excipients or carriers toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). Alternatively,such preparations may contain from about 20% to about 80% activecompound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

When the compositions of this invention comprise a combination of acompound of the Formula (I) described herein and one or more additionaltherapeutic or prophylactic agents, both the compound and the additionalagent should be present at dosage levels of between about 1 to 100%, andmore preferably between about 5 to 95% of the dosage normallyadministered in a monotherapy regimen. The additional agents may beadministered separately, as part of a multiple dose regimen, from thecompounds of this invention. Alternatively, those agents may be part ofa single dosage form, mixed together with the compounds of thisinvention in a single composition.

The said “additional therapeutic or prophylactic agents” includes, butis not limited to, immune therapies (eg. interferon), therapeuticvaccines, antifibrotic agents, anti-inflammatory agents such ascorticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergicagonists and xanthines (e.g. theophylline), mucolytic agents,anti-muscarinics, anti-leukotrienes, inhibitors of cell adhesion (e.g.ICAM antagonists), anti-oxidants (eg N-acetylcysteine), cytokineagonists, cytokine antagonists, lung surfactants and/or antimicrobialand anti-viral agents (eg ribavirin and amantidine). The compositionsaccording to the invention may also be used in combination with genereplacement therapy.

Combination and Alternation Therapy for HCV

It has been recognized that drug-resistant variants of HCV can emergeafter prolonged treatment with an antiviral agent. Drug resistance mosttypically occurs by mutation of a gene that encodes for a protein suchas an enzyme used in viral replication, and most typically in the caseof HCV, RNA polymerase, protease, or helicase.

Recently, it has been demonstrated that the efficacy of a drug against aviral infection, such as HIV, can be prolonged, augmented, or restoredby administering the drug in combination or alternation with a second,and perhaps third, antiviral compound that induces a different mutationfrom that caused by the principal drug. Alternatively, thepharmacokinetics, biodistribution, or other parameter of the drug can bealtered by such combination or alternation therapy. In general,combination therapy is typically preferred over alternation therapybecause it induces multiple simultaneous stresses on the virus.

A compound of the present invention can also be administered incombination or alternation with antiviral agent. Exemplary antiviralagents include ribavarin, interferon, interleukin or a stabilizedprodrug of any of them. More broadly described, the compound can beadministered in combination or alternation with any of the anti-HCVdrugs listed in Table 13 below.

TABLE 13 Table of anti-Hepatitis C Compounds in Current ClinicalDevelopment Drug name Drug category Pharmaceutical Company PEGASYS Longacting interferon Roche pegylated interferon alfa-2a INFERGEN Longacting interferon InterMune interferon alfacon-1 OMNIFERON Long actinginterferon Viragen natural interferon ALBUFERON Long acting interferonHuman Genome Sciences REBIF Interferon Ares-Serono interferon beta-laOmega Interferon Interferon BioMedicine Oral Interferon alpha OralInterferon Amarillo Biosciences Interferon gamma-lb Anti-fibroticInterMune IP-501 Anti-fibrotic InterMune Merimebodib VX-497 IMPDHinhibitor Vertex (inosine monophosphate dehydrogenase) AMANTADINE BroadAntiviral Agent Endo Labs (Symmetrel) Solvay IDN-6556 Apotosisregulation Idun Pharma. XTL-002 Monclonal Antibody XTL HCV/MF59 VaccineChiron CIVACIR Polyclonal Antibody NABI Therapeutic vaccine InnogeneticsVIRAMIDINE Nucleoside Analogue ICN ZADAXIN (thymosin alfa-1)Immunomodulator Sci Clone CEPLENE (histamine) Immunomodulator Maxim VX950/LY 570310 Protease inhibitor Vertex/Eli Lilly ISIS 14803 AntisenseIsis Pharmaceutical/Elan IDN-6556 Caspase inhibitor Idun PharmaceuticalsJTK 003 Polymerase Inhibitor AKROS Pharma Tarvacin Anti-PhospholipidTherapy Peregrine HCV-796 Polymerase Inhibitor ViroPharma/Wyeth CH-6Protease inhibitor Schering ANA971 Isatoribine ANADYS ANA245 IsatoribineANADYS CPG 10101 (Actilon) Immunomodulator Coley Rituximab (Rituxam)Anti-CD2O Genetech/IDEC Monoclonal Antibody NM283 (Valopicitabine)Polymerase Inhibitor Idenix Pharmaceuticals HepX ™-C Monoclonal AntibodyXTL IC41 Therapeutic Vaccine Intercell Medusa Interferon Longer actinginterferon Flamel Technology E-1 Therapeutic Vaccine InnogeneticsMultiferon Long Acting Interferon Viragen BILN 2061 Protease inhibitorBoehringer-Ingelheim TMC435350 Protease inhibitor Tibotec/MedivirTelaprevir (VX-950) Protease inhibitor Vertex Boceprevir (SCH 503034)Protease inhibitor Schering-Plough ACH-1625 Protease inhibitor AchillionABT-450 Protease inhibitor Abbott/Enanta BI-201335 Protease inhibitorBoehringer-Ingelheim PHX-1766 Protease inhibitor Phenomix VX-500Protease inhibitor Vertex MK-7009 protease inhibitor Merck R7227(ITMN-191) protease inhibitor InterMune Narlaprevir (SCH 900518)Protease inhibitor Schering/Merck Alinia (nitazoxanide) To be determinedRomark ABT-072 Polymerase Inhibitor Abbott ABT-333 Polymerase InhibitorAbbott Filibuvir (PF-00868554) Polymerase Inhibitor Pfizer VCH-916Polymerase Inhibitor Vertex R7128 (PSI6130) Polymerase InhibitorRoche/Pharmasset IDX184 Polymerase Inhibitor Idenix R1626 Polymeraseinhibitor Roche MK-3281 Polymerase inhibitor Merck PSI-7851 Polymeraseinhibitor Pharmasset ANA598 Polymerase inhibitor Anadys PharmaceuticalsBI-207127 Polymerase inhibitor Boehringer-Ingelheim GS-9190 Polymeraseinhibitor Gilead VCH-759 Polymerase Inhibitor Vertex Clemizole NS4Binhibitor Eiger Biopharmaceuticals A-832 NS5A inhibitorArrowTherapeutics BMS-790052 NS5A inhibitor Bristol-Myers-Squibb ITX5061Entry inhibitor iTherx GS-9450 Caspase inhibitor Gilead ANA773 TLRagonist Anadys CYT107 Immunomodulator Cytheris SPC3649(LNA-antimiR ™-122) microRNA Santaris Pharma Debio 025 Cyclophilininhibitor Debiopharm SCY-635 Cyclophilin inhibitor Scynexis

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one of ordinary skill in theart. All publications, patents, published patent applications, and otherreferences mentioned herein are hereby incorporated by reference intheir entirety.

Abbreviations

Abbreviations which may be used in the descriptions of the scheme andthe examples that follow are: Ac for acetyl; AcOH for acetic acid; AIBNfor azobisisobutyronitrile; BINAP for2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; Boc₂O fordi-tert-butyl-dicarbonate; Boc for t-butoxycarbonyl; Bpoc for1-methyl-1-(4-biphenylyl)ethyl carbonyl; BtOH for1-hydroxy-benzotriazole; Bz for benzoyl; Bn for benzyl; BocNHOH fortert-butyl N-hydroxycarbamate; t-BuOK for potassium tert-butoxide;Bu₃SnH for tributyltin hydride; BOP for(benzotriazol-1-yloxy)tris(dimethylamino)phos-phoniumHexafluorophosphate; Brine for sodium chloride solution in water; Cbzfor carbobenzyloxy; CDI for carbonyldiimidazole; CH₂Cl₂ fordichloromethane; CH₃ for methyl; CH₃CN for acetonitrile; Cs₂CO₃ forcesium carbonate; CuCl for copper (I) chloride; CuI for copper (I)iodide; dba for dibenzylidene acetone; dppb for diphenylphosphinobutane; DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene; DCC forN,N′-dicyclohexylcarbodiimide; DEAD for diethylazodicarboxylate; DIADfor diisopropyl azodicarboxylate; DIBAL-H for diisobutylaluminiumhydride; DIPEA or (i-Pr)₂EtN for N,N-diisopropylethyl amine; Dess-Martinperiodinane for1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one; DMAP for4-dimethylaminopyridine; DME for 1,2-dimethoxy-ethane; DMF forN,N-dimethylformamide; DMSO for dimethyl sulfoxide; DMT fordi(p-methoxyphenyl)phenylmethyl or dimethoxytrityl; DPPA fordiphenylphosphoryl azide; EDC forN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide; EDC.HCl forN-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride; EtOAc forethyl acetate; EtOH for ethanol; Et₂O for diethyl ether; Fmoc for9-fluorenylmethoxycarbonyl; Grubbs-1 catalyst forbenzylidene-bis(tricyclohexylphosphine)dichlororuthenium; HATU forO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; HCl for hydrogen chloride; HOBT for1-hydroxybenzotriazole; K₂CO₃ for potassium carbonate; n-BuLi forn-butyl lithium; i-BuLi for i-butyl lithium; t-BuLi for t-butyl lithium;PhLi for phenyl lithium; LDA for lithium diisopropylamide; LiTMP forlithium 2,2,6,6-tetramethylpiperidinate; MeOH for methanol; Mg formagnesium; MOM for methoxymethyl; Ms for mesyl or —SO₂—CH₃; Ms₂O formethanesulfonic anhydride or mesyl-anhydride; NaBH₄ for sodiumborohydride; NaBH₃CN for sodium cyanoborohydride; NaN(TMS)₂ for sodiumbis(trimethylsilyl)amide; NaCl for sodium chloride; NaH for sodiumhydride; NaHCO₃ for sodium bicarbonate or sodium hydrogen carbonate;Na₂CO₃ sodium carbonate; NaOH for sodium hydroxide; Na₂SO₄ for sodiumsulfate; NaHSO₃ for sodium bisulfite or sodium hydrogen sulfite; Na₂S₂O₃for sodium thiosulfate; NH₂NH₂ for hydrazine; NH₄HCO₃ for ammoniumbicarbonate; NH₄Cl for ammonium chloride; NMMO for N-methylmorpholineN-oxide; NaIO₄ for sodium periodate; Ni for nickel; OH for hydroxyl;OSO₄ for osmium tetroxide; Pd for palladium; Ph for phenyl; PMB forp-methoxybenzyl; POPd for dihydrogendichlorobis(di-tert-butylphosphinito-κP)palladate(II); Pd₂(dba)₃ fortris(dibenzylidene-acetone) dipalladium (0); Pd(PPh₃)₄ fortetrakis(triphenylphosphine)palladium (0); PdCl₂(PPh₃)₂ fortrans-dichlorobis(triphenyl-phosphine)palladium (II); Pt for platinum;Rh for rhodium; rt for room temperature; Ru for ruthenium; SEM for(trimethylsilyl)ethoxymethyl; TBAF for tetrabutylammonium fluoride; TBSfor tert-butyl dimethylsilyl; TEA or Et₃N for triethylamine; Teoc for2-trimethylsilyl-ethoxy-carbonyl; TFA for trifluoroacetic acid; THF fortetrahydrofuran; TMEDA for N,N,N′,N′-tetramethylethylenediamine; TPP orPPh₃ for triphenyl-phosphine; Troc for 2,2,2-trichloroethyl carbonyl; Tsfor tosyl or —SO₂—C₆H₄CH₃; Ts₂O for tolylsulfonic anhydride ortosyl-anhydride; TsOH for p-tolylsulfonic acid; TMS for trimethylsilyl;or TMSCl for trimethylsilyl chloride.

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes thatillustrate the methods by which the compounds of the invention may beprepared. Starting materials can be obtained from commercial sources orprepared by well-established literature methods known to those ofordinary skill in the art. It will be readily apparent to one ofordinary skill in the art that the compounds defined above can besynthesized by substitution of the appropriate reactants and agents inthe syntheses shown below. It will also be readily apparent to oneskilled in the art that the selective protection and deprotection steps,as well as the order of the steps themselves, can be carried out invarying order, depending on the nature of the variables to successfullycomplete the syntheses below. The variables are as defined above unlessotherwise noted below.

The compounds of the present invention may be prepared via severaldifferent synthetic routes from a variety of 5/6-membered ring fusedheteroaryl, 5-membered ring heteroaryl, and related intermediates. Anexemplary method is shown in Schemes 1, 2, 3, and 4. A retro-synthesisof those title compounds include direct formation of a suitableheterocycle (5/6-membered ring fused heteroaryl or 5-membered ringheteroaryl) optionally with a suitable macrocyclic linkage, followed byattachment of a suitable capping group (such as —C(O)R⁶), plus somefunctional group manipulations in between and/or after. Various5/6-membered ring fused heteroaryl or 5-membered ring heteroarylintermediates are known to those skilled in the art, for example see theencyclopedic volumes edited by A. R. Katrizky, et al, “ComprehensiveHeterocyclic Chemistry” 1984; “Comprehensive Heterocyclic Chemistry II”1996; “Comprehensive Heterocyclic Chemistry III” 2008.

A general synthesis and further elaboration of some 6-membered ringfused with imidazole-related intermediates are summarized in Scheme 1,in which Z is N or CH.

The synthesis starts from the construction of an optionally substitutedimidazopyridine or benzimidazole 1-2, which may be obtained bycondensation of an amino acid or its derivatives 1-1.1 or 1-1.2 with2,3-diaminopyridine or 1,2-diaminobenzene 1-1 under the conditions tothose skilled in the art. The imidazole ring closure may be realizedeither in one pot by heat, optionally in the presence of an acid and/orwith a dehydration reagent such as polyphosphoric acid; or in twosteps: 1) amide formation between diamine 1-1 and amino acid 1-1.1 or1-1.2 in the presence of a condensation reagent such as EDC.HCl, DCC orthe like; or through mixed anhydride approach by reacting acid 1-1.1 or1-1.2 with a chloroformate such as methyl chloroformate, isobutylchloroformate, or the like, in the presence of a base such as TEA,DIPEA, DMAP, N-methylmorpholine, or the like, followed by treating themixed anhydride with diamine 1-1; and 2) the heterocyclic ring closurein the presence of an acid such as acetic acid, sulfuric acid or thelike or a dehydration reagent such as HATU or the like, optionally withheat. Other imidazopyridines or benzimidazoles with more substitutionmay be prepared similarly using the procedures described hereinwith.

The imidazopyridine or benzimidazole 1-2 may be subjected to Suzuki,Stille or related coupling conditions known to those skilled in the art(see reviews: A. Suzuki, Pure Applied Chem., 1991, 63, 419; A. Suzuki,Handbook of Organopalladium Chemistry for Organic Synthesis, 2002, 1,249; A. Anastasia, et al, Handbook of Organopalladium Chemistry forOrganic Synthesis, 2002, 1, 311; F. Bellina, et al, Synthesis, 2004,2419; M. G. Organ, et al, Synthesis 2008, 2776; A. T. Lindhardt, et al,Chem.—A European J., 2008, 14, 8756; E. A. B. Kantchev, et al, Angew.Chem. Int. Ed., 2007, 46, 2768; V. Farina, et al, Advances inMetal-Organic Chem., 1996, 5:1) with different coupling partners toprovide a variety of key intermediates. For example, Sonogashiracoupling between bromide 1-2 and trimethylsilylacetylene can generatealkyne 1-3 after removal of TMS by K₂CO₃ in MeOH. Alternatively, bromide1-2 may be coupled with tributylvinylstanne through Stille reactionconditions known to those skilled in the art to provide alkene 1-4.Analogously, a key allyl intermediates 1-5 may be prepared by Stillereaction from bromide 1-2 with an allylstanne such asallyltributylstanne.

Alternatively, bromide 1-2 may be converted to key intermediate 1-7 byselectively reacting with metallic reagent 1-2.2 under the Suzuki orStille conditions which are known to those skilled in the art. Yetalternatively, intermediate 1-7 may be prepared by treating bromide 1-2with dimetallic agent 1-2.1 to afford organometallic 1-6, followed bycoupling with bromoiodoaryl compound 1-6.1, both may be under thepreviously described Suzuki or Stille reaction conditions. The bromide1-7 may be further converted to organometallic 1-8 with dimetallic agent1-2.1 using the conditions described above to prepare 1-6.

It should be noted that optionally the NH group of all theimidazopyridine or benzimidazole related intermediates listed above maybe protected with an amino protecting group, such as SEM (i.e. SEM-Cl,NaH), Boc, Cbz, Teoc, Troc, or the like.

A typical synthesis of imidazole related intermediates are analogous tothat of the imidazopyridine or benzimidazole intermediates. As shown inScheme 2, bromo-imidazole 2-2 can be synthesized by condensation ofamino acid derived aldehyde 2-1.1 or 2-1.2 and glyoxal in the presenceof methanolic ammonia; followed by bromination of the imidazole ringunder the conditions which are known to those skilled in the art. Thebromination of the imidazole ring may be realized either in one pot byNBS, bromine, 2,4,4,6-tetrabromo-2,5-cyclohexadienone, or the like; orin two steps: 1) dibromide formation in the presence of excessbromination reagent such as NBS, bromine,2,4,4,6-tetrabromo-2,5-cyclohexadienone, or the like, optionally withheat; and 2) reduction of the dibromide to monobromide in the presenceof a reducing reagent such as NaHSO₃, Na₂S₂O₃, Na₂SO₃, or the like.Bromide 2-2 then may be served as a common intermediate furtherelaborable to many other imidazole derivatives using the chemistrydiscussed in Scheme 1. For example, bromide 2-2 may be coupled withallytin or vinyltin or TMS-acetylene to provide intermediate 2-6. Also,bromide 2-2 may be converted to key intermediate 2-4 by selectivelyreacting with metallic reagent 2-2.1 under the Suzuki or Stilleconditions to provide key intermediate 2-4. Yet alternatively,intermediate 2-4 may be prepared by treating bromide 2-2 with dimetallicagent 2-2.2 to afford organometallic 2-5, followed by coupling withbromoiodoaryl compound 2-5.1, both may be under the previously describedSuzuki or Stille reaction conditions. The bromide 2-4 may be furtherconverted to organometallic 2-7 with dimetallic agent 2-4.1 using theconditions described above for the preparation of intermediate 2-5.

Yet alternatively, aryl or heteroaryl bromide 2-4 may also be derivedfrom bromoketone 2-9, which can be prepared from the correspondingketone 2-8 in the presence of a bromination reagent such as NBS,bromine, or the like, optionally in the presence of an acid and/or withheating. Bromoketone 2-9 may be either converted to the correspondingamine 2-11 through azide substitution followed by reduction, or coupledwith protected amino acid 1-1.1 or 1-1.2 in the presence of a base suchas Et₃N or DIPEA to afford keto-ester 2-10. Similarly, amine 2-11 may beconverted to the corresponding keto-amide 2-12 via condensation withappropriate amino acid under standard amide formation conditions. Both2-12 and 2-13 may be transformed to key intermediate 2-4 via heatingwith NH₄OAc under thermal or microwave conditions.

The synthesis of 4,5-disubstituted imidazole related intermediates areanalogous to that described in Scheme 2. Alternatively, these imidazoleintermediates can be synthesized from ketone 2-8a (Scheme 2a) throughnitrosation (sodium nitrite, HCl) to ketooxime 2-9a, which can becyclized with aldehyde 2-1.1 or 2-1.2 to 1-hydroxyimidazole 2-4a in thepresence of ammonia or ammonium hydroxide. Reduction of 2-4a with asuitable reducing reagent such as triethyl phosphite can lead to therequsite imidazole 2-4b.

As shown in Scheme 3, a compound 3-1 containing a hydroxy groupsubstituted at the C4-position of the pyrrolidine ring may beillustrated by intermediates 1-2, 1-3, 1-4, 1-5, 1-7, 2-2, 2-4, and 2-6when U is CH(OH) as shown in Schemes 1 and 2. Oxidation of 3-1 by avariety of oxidation agents such as Dess-Martin periodinane optionallyin the presence of an acid such as acetic acid or camphorsulfonic acidto afford the ketone 3-2. More reagents and conditions for the oxidationof an alcohol to a ketone can be found in Comprehensive Organictransformations, R. C. Larock Ed., Wiley-RCH, 1999, page 1236-1249. 3-2may then serve as a universal intermediate for further derivatization toolefin 3-3, oxime 3-4 and hydrazone 3-5. The olefination of 3-2 may berealized by various types of Wittig Reaction or Peterson Reaction, amore detailed reagents and conditions can be found in ComprehensiveOrganic transformations, R. C. Larock Ed., Wiley-RCH, 1999, page327-350. The olefin 3-3 may be converted to cyclopropane 3-6 through thewell-known Simmons-Smith cyclopropanation, a more detailed reagents andconditions can be found in Name Reactions and Reagents in OrganicSynthesis B. P. Munday, et al Ed., Wiley, 2005, page 600 and J. C.Lorenz, et al, J. Org. Chem., 2004, 69, 327 and references citedtherein.

Suitably substituted analogs of intermediates 1-2, 2-4, 2-4b or thecompounds in Scheme 3 may be used as precursors to make a macrocyclicderivative after suitable manipulations and transformations offunctional groups or protection groups. As illustrated in Scheme 3a withphenyl-imidazole analogs, bromination of ketone 3-1a may lead to bromide3-2a. The latter is then esterified with Boc-protected aminoacid(wherein R^(a) is selected from the group consisting of optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, and alkoxycarbonyl) to afford ketoester 3-3a, whichcan be converted to imidazole 3-4a (wherein PG is an amino protectinggroup) using the chemistry described in Scheme 2. The imidazole moietyin 3-4a may be optionally protected to 3-5a, which can be converted to3-6a in two steps: 1) deprotection of the Boc group and 2) the releasedamine functionality may be acylated with a carboxylic acid (R^(c)COOH,wherein R^(c) is R⁶ as previously defined) under standard acylationconditions, for example a coupling reagent such as HATU in combinationwith an organic base such as DIPEA can be used in this regard. Variouscarboxylic acids including amino acids in racemic or optical form arecommercially available, and/or can be synthesized in racemic or opticalform, see references cited in reviews by D. Seebach, et al, Synthesis,2009, 1; C. Cativiela and M. D. Diaz-de-Villegas, Tetrahedron:Asymmetry, 2007, 18, 569; 2000, 11, 645; and 1998, 9, 3517; andexperimental examples compiled in patent application WO 08/021,927 A2 byC. Bachand, et al, from Bristol-Myers Squibb, Co., which is incorporatedherein by reference. The conversion from 3-5a to 3-6a may optionallyinvolve one or more steps of functional group manipulation, thus R^(b)in 3-6a may be the same as or different from R^(a) as in 3-5a dependingon the interchange of functional groups. These transformation step(s)may include, but are not limited to, alkylation, etherification,esterification, amidation, reduction, oxidation, olefination,halogenation, oximation, and/or hydroxylation. Two reactive groups inR^(b) and R^(c) in 3-6a may undergo an intramolecular reaction to form amacrocyclic structure as seen in 3-7a under appropriate reactionconditions, optionally in the presence of catalyst(s) and/orpromoter(s). The reaction that can be used to succeed thisintramolecular cyclization may include, but not limited toetherification, ester formation, reductive amination, amide formation,carbamate formation, urea formation, ring-closure-metathesis,Pd-catalyzed selective cross-couplings, oximation, various types ofDiels-Alder reaction, and/or radical cyclization. Then the imidazoleprotection group may be optionally removed to 3-8a.

An example of strategies that may be used to form the macrocyclicstructures are illustrated in Scheme 3b, wherein bromophenyl imidazole3-2b can be obtained from ketone 3-1b using the procedures describedabove. 3-2b can be reduced by DIBAL-H to alcohol 3-3b, which is thenserved as a universal intermediate for further transformations. Thus,3-4b may be obtained from 3-3b in three steps: 1) allylation with allylbromide and sodium hydride in DMF; 2) simultaneously deprotection of Bocand SEM with HCl under heat; and 3) capping the released pyrrolidinewith methoxycarbonyl-protected allylglycine. The di-olefin 3-4b can beconverted to macrocyclic olefin 3-5b (wherein the dotted bond may be nilor a single bond) through metal-catalyzed ring-closure-metathesis (RCM),which is well-known to those-in-the-art. Similarly 3-3b can be alkylatedwith propargyl bromide, followed by a) selective deprotection of Boc; b)capping with an appropriately substituted amino acid (wherein thealdehyde group may be protected as acetal); and c) deprotection of theacetal to release the aldehyde moiety, to afford 3-6b. The aldehyde in3-6b may be converted to oxime by hydroxylamine, which can be convertedin situ to its nitrile oxide by NCS type reagent, and the latter mayreact with the triple bond to fulfil the “click” reaction to afford themacrocyclic isoxazole derivative 3-7b after removal of SEM-protection.Alternatively 3-3b can be selectively deprotected and capped with aprotected lysine derivative to compound 3-8b. After removal of Fmocprotection by piperidine, the free hydroxy and amino group may be unitedinto a carbamate group by a reagent such as CDI, phosgene or the like tothe macrocyclic carbamate 3-9b.

Other intermediates with a macrocyclic ring may be prepared by usingstrategies similar to that described in Scheme 3a and 3b. As exemplifiedin Scheme 3c, wherein bromophenyl imidazole 3-2c can be obtained fromketone 3-1c using the procedures described above. 3-2c can be reduced byNH₄OAc to alcohol 3-3c, which is then served as a universal intermediateto give the macrocyclic structures 3-5c, 3-7c and 3-9c.

Other intermediates with a macrocyclic ring may be prepared by usingstrategies similar to that described in Scheme 3a, 3b and 3c. Asexemplified in Scheme 3d, wherein bromophenyl imidazole 3-2d can beobtained from ketone 3-1d using the procedures described above. 3-2d canbe deprotected Boc group to obtain 3-3d, which is then served as auniversal intermediate to give the macrocyclic structures 3-5d, 3-7d and3-9d.

With a variety of suitably substituted imidazopyridines, benzimidazolesand imidazoles such as those listed in Schemes 1-3,2a, 3a, 3b, 3c and 3din hand, the compounds of the present invention may be prepared throughvarious coupling strategy or a combination of strategies to connect twofragments, optionally with a suitable cyclic or acyclic linker orformation of a cyclic or acyclic linker. The said strategy may include,but not limited to, Stille coupling, Suzuki coupling, Sonogashiracoupling, Heck coupling, Buchwald amidation, Buchwald amination, amidecoupling, ester bond formation, William etherification, Buchwaldetherification, alkylation, pericyclic reaction with differentvariations, or the like.

An example of the strategies that may be used to prepare the compoundsof the present invention is shown in Scheme 4. Both iodide 4-1.1 and itscorresponding boronate derivative 4-1.2 can be prepared using similarprocedures described previously. The bromide 3-5d-1 can be coupled withboronate 4-1.2 under Suzuki condition in the presence of a Pd-catalystto generate a core structure 4-2. Compound 4-2 then may be served as acommon intermediate for further derivatizations to the title compoundsI-1 using the procedures described in Schemes 3a, 3b, 3c, and 3d.

Alternatively, as shown in Scheme 4a, the compounds of the presentinvention (for example I-1) may also be derived from key intermediates4-1.2a and 3-5d-1 using the Suzuki coupling procedures describedpreviously. The intermediate 4-1.2a has the desired acyl group alreadyinstalled from 4-1.1 using similar sequences shown in Scheme 3b, 3c and3d.

Yet alternatively, as shown in Scheme 4b, the compounds of the presentinvention (for example I-1a) may also be derived from key intermediate4-3 after Suzuki coupling of 4-1.2b and 3-2d using the proceduresdescribed previously. Compound 4-3 can be converted to di-olefin 4-4 ina few steps: a) selectively deprotected to alcohol; b) allylated toallylic ether; c) deprotected Boc and SEM; and d) capped with acarbamate-protected allylglycine, using the procedures describedpreviously. As discussed earlier, the di-olefin 4-4 can be converted tothe title compound I-1a through RCM to macrocyclic intermediate 4-5followed by de-Cbz under hydrogenation condition and capping with anacyl derivative (such as R⁶COOH), all using the procedures describedearlier.

The compounds of the present invention containing five-memberedheteroaryl other than imidazole may be prepared using similar proceduresdescribed above in Schemes 1-4 and 4a. For example, some intermediatescontaining a desired, suitably substituted five-membered heteroaryl havebeen published in US 2008/0311075A1 by C. Bachand, et al fromBristol-Myers Squibb, Co., which is incorporated by reference. Theseintermediates are compiled in the following table.

TABLE 14

The synthesis of the compounds of the present invention involves5/6-membered fused heteroaryl intermediates other than benzimidazoles,various 5/6-membered fused heteroaryl are known in the literature. Thesynthesis of other 5/6-membered fused heteroaryl intermediates dependson the chemical features of each structure. For example, a typicalsynthesis of indole intermediate is illustrated in Scheme 5. Thecommercially available bromoiodoaniline 5-1 may be coupled to thecommercially available acetylene 5-1.1 under the Sonogashira conditionsto give phenylacetylene 5-2. The latter may be cyclized to indole 5-3under heat or microwave condition in the presence of a copper catalyst.

Some intermediates and/or precursors that may be used for the synthesisof the compounds of the present invention have also been disclosed inthe following patent publications: WO 2009/102568A1; WO 2009/102633A1;WO 2010/065668A1; WO 2010/065674A1; WO 2010/065681A1; WO 2010/09677A1;WO 2010/111483A1; WO 2010/111534A1; WO 2010/111673A1; WO 2010/120935A1;WO 2010/132538A1A1; WO 2010/132601A1; WO 2010/138368A1; WO2010/138488A1; WO 2010/138790A1; WO 2010/138791A1; WO 2010/144646A2; US2010/0215618A1; WO 2011/004276A1; WO 2011/028596A1; WO 2011/060000A1; WO2011/066241A1; WO 2011/075439A1; WO 2011/075615A1; and WO 2011/091417A1,which are each incorporated by reference herein.

It will be appreciated that, with appropriate manipulation andprotection of any chemical functionality, synthesis of compounds ofFormula (I) is accomplished by methods analogous to those above and tothose described in the Experimental section. Suitable protecting groupscan be found, but are not restricted to, those found in T W Greene and PG M Wuts “Protective Groups in Organic Synthesis”, 3rd Ed (1999), JWiley and Sons.

In some embodiments, the invention is directed to a process of making acompound described herein comprising:

-   -   i) preparing a compound of Formula (I-a-1):

-   -   via a transition-metal catalyzed cross-coupling reaction,        ring-closure metathesis or other intramolecular ring-closure        reaction;

wherein:

W is an optionally substituted 5-membered heteroaryl containing one ormore nitrogen or optionally substituted 5/6-membered fused heteroaryl,wherein the 5-membered ring of said 5/6-membered fused heteroarylcontains one or more nitrogen and is attached to the carbon atom towhich R³ is also attached, and wherein the 6-membered ring of said5/6-membered fused heteroaryl is attached to group B, L or A and is arylor heteroaryl;

Q¹ is

Alternatively, G and Q¹ can be taken together to form a group selectedfrom:

X³ and X⁴ at each occurrence are each independently N or C(R¹²); and R¹²at each occurrence is independently hydrogen, halogen, hydroxy,optionally substituted C₁-C₄ alkyl or O(C₁-C₄ alkyl); Z^(a) isindependently an amino protecting group or —C(O)—R⁶; wherein R⁶ is C₁-C₈alkyl optionally substituted with amino, hydroxy, protected amino, orO(C₁-C₄ alkyl); and A, B, G, L, U, X¹, X², Y, L¹, L², L³, L⁴, L⁵, L⁶,L⁷, L⁸, L⁹, R¹, R^(3a), R⁵, R^(7a) and R^(7b) are as defined in claim 1;

-   -   ii) when Q¹ is

-   -    wherein Z^(a) is an amino protecting group, selectively        deprotecting a compound of Formula (I-a-1) to give the        corresponding amine of Formula (I-b-1):

and

-   -   iii) Capping the released amino group of a compound of Formula        (I-b-1) with LG-C(O)—R⁶, wherein LG is a leaving group; to give        the compound of Formula (I-c-1):

In certain aspects, the invention is directed to the process describedabove wherein the intramolecular ring-closure reaction is a type ofDiels-Alder reaction, amide (lactam) formation, reductive amination,oximation, ester formation (lactonization), carbamate or urea formation.

All references cited herein, whether in print, electronic, computerreadable storage media or other form, are expressly incorporated byreference in their entirety, including but not limited to, abstracts,articles, journals, publications, texts, treatises, internet web sites,databases, patents, and patent publications.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Although the invention has been described with respect to variouspreferred embodiments, it is not intended to be limited thereto, butrather those skilled in the art will recognize that variations andmodifications may be made therein which are within the spirit of theinvention and the scope of the appended claims.

Example 344

Step 344a. To a solution of dimethyl sulfoxide (0.98 mL, 13.82 mmol) indichloromethane (12 mL) at −78° C. was added oxalyl chloride (0.60 mL,6.911 mmol) dropwise. After 20 min at −78° C., a solution of(S)-tert-butyl 2-(tert-butoxycarbonylamino)-5-hydroxypentanoate(prepared according to ARKIVOC, 2003, 8, 180; 1.000 g, 3.456 mmol) indichloromethane (7 mL) was added. The mixture was stirred at −78° C. for30 min before triethylamine (3.85 mL, 27.65 mmol) was added. After 20min at −78° C., the milky mixture was allowed to gradually warm up toroom temperature and stirred at room temperature for 30 min. SaturatedNH₄Cl solution was added to quench the reaction. The mixture waspartitioned (H₂O—EtOAc). The organic phase was washed with brine, dried(Na₂SO₄), filtered and concentrated to afford the desired compound as ayellow oil (1.013 g), which was used without further purification.Step 344b. To a suspension of PPh₃MeBr (6.173 g, 17.28 mmol) in THF (60mL) at 0° C. was added t-BuOK (1 M in THF, 17.28 mL, 17.28 mmol). Themixture was stirred at 0° C. for 5 min and then at room temperature for1 hour. It was cooled back down to 0° C. before a solution of thecompound from step 344a (1.013 g, 3.456 mmol at most) in THF (12 mL) wasadded. The mixture was allowed to gradually warm up to room temperatureand stirred at room temperature overnight. Saturated NH₄Cl solution wasadded to quench the reaction. The resultant mixture was evaporated. Theresidue was partitioned (EtOAc—H₂O). The organics were washed withbrine, dried (Na₂SO₄), filtered and evaporated. The residue was purifiedby flash column chromatography (silica, hexanes-ethyl acetate) to givethe desired compound as a colorless oil (0.456 g, 46% over 2 steps).ESIMS m/z=286.25 [M+H]⁺. (note: Epimerization happened at this stage.).Step 344c. A solution of the compound from step 344b (0.456 g, 1.598mmol) in dichloromethane (1 mL) and trifluoroacetic acid (5 mL) wasstirred at room temperature for 5 hour before being evaporated. Theresidue was co-evaporated with dichloromethane, hexanes, dried undervacuum to afford the desired compound as a light yellow solid, which wasused without further purification. ¹H NMR (D₂O) δ (ppm) 5.78-5.70 (m,1H), 5.02 (dd, J=17.2, 1.3 Hz, 1H), 4.96 (d, J=10.2 Hz, 1H), 3.87 (t,J=6.3 Hz, 1H), 2.10-2.04 (m, 2H), 1.98-1.91 (m, 1H), 1.89-1.82 (m, 1H).Step 344d. A mixture of the crude compound from step 344c (1.598 mmol atmost), NaOH (1 M in H₂O, 3.20 mL, 3.196 mmol) and Na₂CO₃ (0.186 g, 1.758mmol) at 0° C. was treated with methyl chloroformate (0.13 mL, 1.734mmol). Dioxane (1 mL) was added. After 10 minutes at 0° C., the solutionwas stirred at room temperature for 3.5 hours before being evaporated toremove dioxane. The residue was extracted with ether. The aqueous layerwas acidified with 3N HCl at 0° C. to pH ˜2 before being extracted withdichloromethane and then EtOAc. The combined organic layers were washedwith brine, dried (Na₂SO₄), filtered and concentrated. The residue wasdried under vacuum to afford the desired compound as a yellow oil (0.285g, 95% over 2 steps). ¹H NMR (CD₃OD) δ (ppm) 5.87-5.79 (m, 1H), 5.06(dd, J=17.1, 1.3 Hz, 1H), 5.01 (d, J=10.2 Hz, 1H), 4.15 (dd, J=9.3, 4.6Hz, 1H), 3.67 (s, 3H), 2.26-2.11 (m, 2H), 1.96-1.89 (m, 1H), 1.79-1.71(m, 1H).Step 344e. To a solution of Boc-Homoser-OH (0.500 g, 2.281 mmol) in DMF(10 mL) at −15° C. was added sodium hydride (60% in mineral oil, 0.228g, 5.702 mmol). The suspension was allowed to gradually warm up to roomtemperature and stirred at room temperature for 20 min before beingcooled down to 0° C. Allylbromide (0.21 mL, 2.395 mmol) was added. After30 min at 0° C., the resulting mixture was stirred at room temperaturefor 15 hours before being quenched with water at 0° C. The residue wasextracted with ether. The aqueous layer was acidified with 3N HCl at 0°C. to pH ˜2 before being extracted with dichloromethane and then EtOAc.The combined organic layers were washed with brine, dried (Na₂SO₄),filtered and concentrated. The residue was dried under vacuum to affordthe desired compound as a colorless oil (0.674 g), which was usedwithout further purification. ESIMS m/z=282.19 [M+Na]⁺.Step 344f. To a solution of the compound from step 344e (0.674 g, 2.281mmol at most) and 2,4′-dibromoacetophenone (0.634 g, 2.281 mmol) inacetonitrile (15 mL) was added triethylamine (0.64 mL, 4.562 mmol) atroom temperature. The resulting mixture was stirred at room temperatureovernight before the volatiles were evaporated. The residue was purifiedby flash column chromatography (silica, EtOAc-hexanes) to give thedesired compound as a white solid (0.613 g, 59% over 2 steps). ESIMSm/z=456.14, 458.14 [M+H]⁺.Step 344g. A mixture of the compound from step 344f (0.613 g, 1.343mmol) and ammonium acetate (1.139 g, 14.78 mmol) in xylenes (18 mL) washeated at 140° C. with a microwave for 80 min before being allowed tocool down and partitioned between aqueous NaHCO₃ and EtOAc. The organicphase was washed with brine, dried (Na₂SO₄), filtered and concentrated.The residue was purified by flash column chromatography (silica,EtOAc-hexanes) to afford the desired compound as a yellow foam (0.507 g,87%). ESIMS m/z=436.08, 438.08 [M+H]⁺.Step 344h. To a solution of the compound from step 344g (0.200 g, 0.458mmol) in dichloromethane (3 mL) was added hydrogen chloride (4 M in1,4-dioxane, 3 mL). The mixture was stirred at room temperature for 20min before all volatiles were removed to afford the crude desiredcompound as a yellow solid, which was used directly for the next stepwithout further purification.Step 344i. A mixture of the crude compound from step 344h (0.458 mmol atmost) and the compound from step 1d (94.4 mg, 0.504 mmol) inacetonitrile (8 mL) was treated with HATU (0.174 g, 0.458 mmol) in thepresence of DIPEA (0.80 mL, 4.584 mmol) for 1 hour at room temperaturebefore the volatiles were evaporated off. The residue was purified byflash column chromatography (silica, EtOAc-hexanes) to give the desiredproduct as a yellow foam (0.230 g, 100% over 2 steps). ESIMS m/z=505.12,507.12 [M+H]⁺.Step 344j. To a solution of the compound from step 344i (0.230 g, 0.458mmol) in toluene (200 mL) was added Zhan-1B catalyst (67.1 mg, 91.6μmol). The mixture was degassed at 0° C. and heated at 60° C. under N₂for 2 hours before all volatiles were evaporated. The residue waspurified by chromatography (silica, EtOAc-hexanes) to afford the desiredcompound as a brown solid (59.7 mg, 28%). ESIMS m/z=477.11, 479.11[M+H]⁺.Step 344k. To a mixture of 2,4′-dibromoacetophenone (5.00 g, 18.0 mmol)and N-Boc-L-proline (3.87 g, 18.0 mmol) in CH₃CN (60 mL) was addedtriethylamine (5.40 mL, 37.8 mmol) slowly. The mixture was stirred at rtuntil the disappearance of the starting material. The volatiles wereevaporated and the residue was partitioned (EtOAc—water). The organicswere washed with brine, dried (Na₂SO₄), filtered and evaporated. Theresidue was purified by chromatography (silica, hexanes-ethyl acetate)to give the desired compound as a light yellow foam (6.73 g, 91%). ¹HNMR (CDCl₃) 7.76 (t, J=8.0 Hz, 2H), 7.63 (dd, J=5.0, 8.5 Hz, 2H), 5.51,5.16 (2d, J=16.0 Hz, 1H), 5.32, 5.28 (2d, J=16.5 Hz, 1H), 4.48, 4.40(dd, J=5.0, 8.5 Hz, 1H), 3.56 (m, 1H), 3.43 (m, 1H), 2.30 (m, 2H), 2.06(m, 1H), 1.92 (m, 1H), 1.46, 1.43 (2s, 9H).Step 344l. To a solution of the compound from step 344k (6.73 g, 16.3mmol) in toluene (100 mL) was added ammonium acetate (25.1 g, 0.327 mol)and the mixture was heated at 100° C. for 14 hours. The volatiles wereevaporated and the residue was partitioned (EtOAc—aq. NaHCO₃). Theorganics were washed with brine, dried (Na₂SO₄), filtered andevaporated. The residue was purified by chromatography (silica,hexanes-ethyl acetate) to give the desired compound as a yellow foam(6.10 g, 95%). ESIMS m/z=392.24, 394.24 [M+H]⁺. ¹H NMR (CDCl₃) 7.57 (bs,1H), 7.48 (m, 3H), 7.23 (s, 1H), 4.97 (m, 1H), 3.42 (m, 2H), 2.99 (m,1H), 2.16 (m, 2H), 1.97 (m, 1H), 1.46 (s, 9H).Step 344m. To a mixture of the compound from step 344l (1.00 g, 2.55mmol), bis(pinacolato)diboron (1.35 g, 5.33 mmol) and potassium acetate(0.640 g, 6.53 mmol) in 1,4-dioxane (20 mL) was added Pd(PPh₃)₄ (0.147g, 0.128 mmol). The mixture was degassed and heated at 80° C. under N₂for 14 hours. The volatiles were evaporated and the residue waspartitioned (EtOAc—water). The organics were washed with brine, dried(Na₂SO₄), filtered and evaporated. The residue was purified bychromatography (silica, hexanes-ethyl acetate) to give the desiredcompound as a light yellow solid (0.978 g, 87%). ESIMS m/z=440.39[M+H]⁺. ¹H NMR (CDCl₃) 11.03, 10.55 (2s, 1H), 7.79 (m, 3H), 7.45 (m,1H), 7.26 (m, 1H), 4.97 (m, 1H), 3.41 (m, 2H), 3.06, 2.91 (2m, 1H), 2.17(m, 2H), 1.97 (m, 1H), 1.49 (s, 9H), 1.35 (s, 12H).Step 344n. To a mixture of the compounds from step 344j (59.7 mg, 0.125mmol), and step 344m (82.4 mg, 0.188 mmol) and NaHCO₃ (42.0 mg, 0.500mmol) in DME (4 mL) and H₂O (1.3 mL) was added Pd(PPh₃)₄ (14.5 mg, 12.5μmol). The mixture was degassed at 0° C. and then heated at 97° C. underN₂ for 3 hours. The volatiles were evaporated. The residue was taken upin dichloromethane and filtered. The filtrate was directly purified bychromatography (silica, hexanes-ethyl acetate-MeOH) to give a mixture ofthe title compounds as a yellow solid (47.6 mg, 54%). ESIMS m/z=710.41[M+H]⁺.

Example 345

Step 345a. A solution of the compound from example 344 (47.6 mg, 67.1μmol) in dichloromethane (2 mL) was treated with hydrogen chloride (4 Min 1,4-dioxane, 2 mL) at room temperature for 30 minutes. The volatileswere evaporated off to give the crude desired compound as a yellowsolid, which was used directly in the next step.Step 345b. A mixture of the crude compound from step 345a (67.1 μmol atmost) and (5)-(methoxycarbonyl)amino-3-methyl-butyric acid (preparedaccording to WO 2008/021927, 11.7 mg, 67.1 μmol) in DMF (3 mL) wastreated with HATU (25.5 mg, 67.1 μmol) in the presence of DIPEA (0.11mL, 0.671 mmol) for 30 minutes at room temperature. The volatiles wereevaporated off. The residue was purified by flash column chromatography(silica, silica, hexanes-EtOAc-MeOH) to give a mixture of the titlecompounds as an off-white solid (49.0 mg, 95% over 2 steps). ESIMSm/z=767.47 [M+H]⁺.

Example 346

Step 346a. To a solution of the compound from example 345 (16.3 mg, 21.3μmol) in MeOH (4 mL) was added palladium hydroxide (20 wt % on carbon, 8mg). The resulting mixture was stirred under hydrogen (60 psi) at roomtemperature for 20 hours before being diluted with dichloromethane andfiltered through a plug of celite. The filtrate was concentrated. Theresidue was purified by HPLC (varian column, MeOH—H₂O) to give a mixtureof the title compounds as a light yellow solid (7.1 mg, 44%). ESIMSm/z=769.35 [M+H]⁺.

The title compounds of examples 1-343 and 347-354 may be prepared usingthe chemistry described above.

TABLE 1 Compounds 1-219.

Entry

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

TABLE 2 Compounds 220-229.

Entry R R′ R″ U 220 Me H H CH₂ 221 H H H CF₂ 222 Me H H S 223 H H H

224 H Me H CH₂ 225 H H H

226 H Ph H CH₂ 227 H H H

228 H H Ph CH₂ 229 H H H

TABLE 3 Compounds 230-239.

Entry R R′ R″ 230 Me H H 231 H CO₂Me H 232 H F H 233 H H CO₂Me 234 H H F235 H OMe H 236 H Cl H 237 H H OMe 238 H H Cl 239 H CF₃ H

TABLE 4 Compounds 240-249.

Entry R R′ R″ R′′′ 240 F H H H 241 F F H H 242 Me H H H 243 Me Me H H244 H H Me Me 245 H H Et Et 246 CF₃ H H H 247 CF₃ H CF₃ H 248 Cl H H H249 Cl H Cl H

TABLE 5 Compounds 250-264.

Entry R 250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

TABLE 6 Compounds 265-282.

Entry A^(a) 265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

TABLE 7 Compounds 283-303.

Entry A^(a) 283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

TABLE 8 Compounds 304-315.

Entry G^(g) 304

305

306

307

308

309

310

311

312

313

314

315

TABLE 9 Compounds 316-333.

Entry L^(a)—L^(b)—L^(c)—R^(d) 316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

TABLE 10 Compounds 334-343.

Compound 334

Compound 335

Compound 336

Compound 337

Compound 338

Compound 339

Compound 340

Compound 341

Compound 342

Compound 343

TABLE 12 Compounds 347-354.

Compound 347

Compound 348

Compound 349

Compound 350

Compound 351

Compound 352

Compound 353

Compound 354

Biological Activity 1. HCV Replicon Cell Lines

HCV replicon cell lines (kindly provided by R. Bartenschlager) isolatedfrom colonies as described by Lohman et al. (Lohman et al. (1999)Science 285: 110-113, expressly incorporated by reference in itsentirety) and used for all experiments. The HCV replicon has the nucleicacid sequence set forth in EMBL Accession No.: AJ242651, the codingsequence of which is from nucleotides 1801 to 8406.

The coding sequence of the published HCV replicon was synthesized andsubsequently assembled in a modified plasmid pBR322 (Promega, Madison,Wis.) using standard molecular biology techniques. One replicon cellline (“SGR 11-7”) stably expresses HCV replicon RNA which consists of(i) the HCV 5′UTR fused to the first 12 amino acids of the capsidprotein, (ii) the neomycin phosphotransferase gene (neo), (iii) the IRESfrom encephalomyocarditis virus (EMCV) and (iv) HCV NS2 to NS5B genesand the HCV 3′UTR. Another replicon cell line (“Huh-luc/neo-ET”)described by Vrolijk et. Al. (Vrolijk et. Al. (2003) Journal ofVirological Methods 110:201-209, expressly incorporated by reference inits entirety) stably expresses HCV replicon RNA which consists of (i)the HCV 5′UTR fused to the first 12 amino acids of the capsid protein,(ii) the firefly luciferase reporter gene, (iii) the ubiquitin gene,(iv) the neomycin phosphotransferase gene (neo), (v) the IRES fromencephalomyocarditis virus (EMCV) and (vi) HCV NS3 to NS5B genes thatharbor cell culture adaptive mutations (E1202G, T12801, K1846T) and theHCV 3′UTR.

These cell lines are maintained at 37° C., 5% CO₂, 100% relativehumidity in DMEM (Cat#11965-084, Invitrogen), with 10% fetal calf serum(“FCS”, Invitrogen), 1% non-essential amino acids (Invitrogen), 1% ofGlutamax (Invitrogen), 1% of 100× penicillin/streptomycin(Cat#15140-122, Invitrogen) and Geneticin (Cat#10131-027, Invitrogen) at0.75 mg/ml or 0.5 mg/ml for 11-7 and Huh-luc/neo-ET cells, respectively.

2. HCV Replicon Assay—qRT-PCR

EC₅₀ values of single agent compounds were determined by HCV RNAdetection using quantitative RT-PCR, according to the manufacturer'sinstructions, with a TAQMAN® One-Step RT-PCR Master Mix Reagents Kit(Cat#AB 4309169, Applied Biosystems) on an ABI Model 7500 thermocycler.EC₅₀ values of combinations are similarly determined by HCV RNAdetection using quantitative RT-PCR. The TAQMAN primers to use fordetecting and quantifying HCV RNA obtained from Integrated DNATechnologies. HCV RNA is normalized to GAPDH RNA levels in drug-treatedcells, which is detected and quantified using the Human GAPDH EndogenousControl Mix (Applied Biosystems, AB 4310884E). Total cellular RNA ispurified from 96-well plates using the RNAqueous 96 kit (Ambion,Cat#AM1812). Chemical agent cytotoxicity is evaluated using an MTS assayaccording to the manufacturer's directions (Promega).

3. HCV Replicon Assay—Luciferase

Since clinical drug resistance often develops in viral infectionsfollowing single agent therapies, there is a need to assess theadditive, antagonistic, or synergistic properties of combinationtherapies. We use the HCV replicon system to assess the potential use ofthe compound of the present invention or in combination therapies withInterferon alpha, cyclosporine analogs and inhibitors targeting otherHCV proteins. The acute effects of a single or combinations of drugs arestudied in the “Huh-luc/neo-ET” replicon with each chemical agenttitrated in an X or Y direction in a 6 point two-fold dilution curvecentered around the EC50 of each drug. Briefly, replicon cells areseeded at 7,000 cells per well in 90 ul DMEM (without phenol red,Invitrogen Cat.#31053-036) per well with 10% FCS, 1% non-essential aminoacids, 1% of Glutamax and 1% of 100× penicillin/streptomycin andincubated overnight at 37° C., 5% CO₂, 100% relative humidity. 16-20 hafter seeding cells, test compounds previously solubilized and titratedin dimethyl sulfoxide (“DMSO”) from each X plate and Y plate are diluted1:100 in DMEM (without phenol red, Invitrogen Cat.#31053-036) with 10%FCS, 1% non-essential amino acids, 1% of Glutamax and 1% of 100×penicillin/streptomycin and added directly to the 96-well platecontaining cells and growth medium at a 1:10 dilution for a finaldilution of compound and DMSO of 1:1000 (0.2% DMSO final concentration).Drug treated cells are incubated at 37° C., 5% CO₂, 100% relativehumidity for 72 hours before performing a luciferase assay using 100 ulper well BriteLite Plus (Perkin Elmer) according to the manufacturer'sinstructions. Data analysis utilizes the method published by Prichardand Shipman (Antiviral Research, 1990. 14:181-205). Using this method,the combination data are analyzed for antagonistic, additive, orsynergistic combination effects across the entire combination surfacecreated by the diluted compounds in combination.

The compounds of the present invention may inhibit HCV by mechanisms inaddition to or other than NS5A inhibition. In one embodiment thecompounds of the present invention inhibit HCV replicon and in anotherembodiment the compounds of the present invention inhibit NS5A.

The compounds of the present invention can be effective against the HCV1b genotype. It should also be understood that the compounds of thepresent invention can inhibit multiple genotypes of HCV. In oneembodiment compound of the present invention are active against the 1a,1b, 2a, 2b, 3a, 4a, and 5a genotypes. Table 15 shows the EC₅₀ values ofrepresentative compounds of the present invention against the HCV 1bgenotype from the above described qRT-PCR or luciferase assay. EC₅₀ranges against HCV 1a or 1b are as follows: A>1 nM; B 100-1000 nM; C<100pM.

TABLE 15 Genotype-1a or 1b replicon EC₅₀ Example Range 1a EC₅₀ ExampleRange 1b EC₅₀ Example Range 1a EC₅₀ 345 A 6.2 nM 345 C 98 pM 346 A 2.2nM

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed:
 1. A compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: A is absent orindependently a monocyclic or polycyclic group independently selectedfrom the group consisting of aryl, heteroaryl, heterocyclic, C₃-C₈cycloalkyl, and C₃-C₈ cycloalkenyl, each optionally substituted; B isabsent or a monocyclic or polycyclic group independently selected fromthe group consisting of aryl, heteroaryl, heterocyclic, C₃-C₈cycloalkyl, and C₃-C₈ cycloalkenyl, each optionally substituted; L isabsent or an aliphatic group; wherein at least one of A, B and L ispresent; W is —C(O)NH— or an optionally substituted 5-memberedheteroaryl containing one or more nitrogen atoms or an optionallysubstituted 5/6-membered fused heteroaryl, wherein the 5-membered ringof said 5/6-membered fused heteroaryl contains one or more nitrogenatoms and is attached to the carbon atom to which R^(3a) is alsoattached, and wherein the 6-membered ring of said 5/6-membered fusedheteroaryl is attached to group B, L or A and is aryl or heteroaryl;Alternatively groups W and B are taken together to form a fusedtricyclic system; G is absent, —C(O)NH—, an optionally substituted5-membered heteroaryl containing one or more nitrogen atoms or anoptionally substituted 5/6-membered fused heteroaryl, wherein the5-membered ring of said 5/6-membered fused heteroaryl contains one ormore nitrogen atoms and is attached to group Q, and wherein the6-membered ring of said 5/6-membered fused heteroaryl is attached to oneof groups A, L or B and is aryl or heteroaryl; Alternatively, groups Gand A are taken together to form a fused tricyclic system; Q ishydrogen,

Alternatively, G and Q can be taken together to form a group selectedfrom:

D is independently a monocyclic or polycyclic group independentlyselected from the group consisting of aryl, heteroaryl, heterocyclic,C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkenyl, each optionally substituted;preferably, B is optionally substituted aryl or optionally substitutedheteroaryl; E is an optionally substituted 5-membered heteroarylcontaining one or more nitrogen atom; X¹ at each occurrence isindependently N or C(R¹¹); X² at each occurrence is independently N(R¹),O or S; X³ and X⁴ are each independently selected from N or C(R¹²); R¹at each occurrence is independently hydrogen, hydroxy, O(C₁-C₄ alkyl) oroptionally substituted C₁-C₄ alkyl; R¹¹ at each occurrence isindependently hydrogen, halogen or optionally substituted C₁-C₄ alkyl;R¹² at each occurrence is independently hydrogen, halogen, hydroxy,optionally substituted C₁-C₄ alkyl, or optionally substituted O(C₁-C₄alkyl); L¹ and L³ are each independently absent or an aliphatic group,wherein at least one of L¹ and L³ is present; L⁴ and L⁶ are eachindependently absent or an aliphatic group, wherein at least one of L⁴and L⁶ is present; L⁷ and L⁹ at each occurrence are each independentlyabsent or an aliphatic group, wherein at least one of L⁷ and L⁹ ispresent; L², L⁵, and L⁸ at each occurrence are each independentlyabsent, or selected from the group consisting of aryl, heteroaryl,heterocyclic, C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkenyl, each optionallysubstituted; wherein -L¹-L²-L³- together form a linker of from 6 to 16bond lengths; wherein -L⁴-L⁵-L⁶- together form a linker of from 8 to 18bond lengths; wherein -L⁷-L⁸-L⁹-R⁶— together form a linker of from 8 to18 bond lengths; Y at each occurrence is independently C(O) or S(O)₂;R^(3a), R³ and R⁴ at each occurrence are each independently selectedfrom the group consisting of hydrogen, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈ alkenyl, and optionally substitutedC₃-C₈ cycloalkyl; alternatively, R^(3a) and L⁷ or R³ and R⁴ are takentogether with the carbon atom to which they are attached to formoptionally substituted C₃-C₈ cycloalkyl or optionally substitutedheterocyclic; R⁵ at each occurrence is independently hydrogen,optionally substituted C₁-C₈ alkyl, or optionally substituted C₃-C₈cycloalkyl; Alternatively R³, R⁴ and R⁵ are taken together with thecarbon and nitrogen atom to which they are attached to form

U is absent or selected from the group consisting of O, S, S(O), SO₂,NC(O)—(C₁-C₄ alkyl), C(O), protected carbonyl, OCH₂, OCH₂CH₂, SCH₂,SCH₂CH₂, C(R⁷)₂, C(R⁷)₂C(R⁷)₂, and C═C(R²)₂; R² at each occurrence isindependently hydrogen, halogen, optionally substituted C₁-C₄ alkyl,optionally substituted aryl, or optionally substituted heteroaryl; R⁷ ateach occurrence is independently selected from the group consisting ofhydrogen, halogen, cyano, hydroxy, O(C₁-C₄ alkyl), S(C₁-C₄ alkyl), aminooptionally substituted with one or two C₁-C₄ alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted C₁-C₄ alkyl, and optionally substituted C₃-C₈ cycloalkyl;Alternatively two geminal R⁷ groups are taken together with the carbonatom to which they are attached to form a spiro, optionally substituted3- to 7-membered cyclic group selected from the group consisting ofC₃-C₇ cycloalkyl, C₃-C₇ cycloalkenyl or 3- to 7-membered heterocyclicring; R^(7a) and R^(7b) at each occurrence are each independentlyselected from the group consisting of hydrogen, optionally substitutedaryl, optionally substituted C₁-C₄ alkyl, and optionally substitutedC₃-C₈ cycloalkyl; Alternatively, CHR^(7a)—U or CHR^(7b)—U are takentogether to form a group selected from CH═CH, fused and optionallysubstituted C₃-C₈ cycloalkyl, fused and optionally substituted aryl, orfused and optionally substituted heterocyclic; Yet alternatively, U,R^(7a), and R^(7b) are taken together with the carbon atoms to whichthey are attached to form a bridged, optionally substituted 4- to7-membered cyclic group selected from the group consisting of C₄-C₇cycloalkyl, C₄-C₇ cycloalkenyl and 4- to 7-membered heterocyclic; and R⁶at each occurrence is independently selected from the group consistingof O(C₁-C₈ alkyl), amino, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, heterocyclic, aryl, andheteroaryl, each optionally substituted.
 2. The compound of claim 1,represented by Formula (Ia) or (Ib):

wherein X¹ is N, X² is NH, X³ and X⁴ are each independently N or CH; ora pharmaceutically acceptable salt thereof.
 3. The compound of claim 2,represented by Formula (Ia-1) or (Ib-1):

wherein: A and B at each occurrence are each independently absent,optionally substituted aryl, or optionally substituted heteroaryl; L isabsent or selected from the group consisting of O, —NH—, —C(O)—,—C(O)NH—, C₁-C₄ alkyl, C₂-C₄ alkenyl, and C₂-C₄ alkynyl, —(C₁-C₄alkyl)-NH—(C₁-C₄ alkyl)- and heterocyclic, each optionally substituted;at least one of A, B and L is present; L⁷ and L⁹ is each independently alinear aliphatic group; and one of L⁷ and L⁹ is optionally absent; R⁵ ishydrogen or optionally substituted C₁-C₄ alkyl; R⁶ at each occurrence isindependently C₁-C₈ alkyl optionally substituted with amino, halogen,hydroxy, protected amino or optionally substituted O(C₁-C₄ alkyl); and Gis absent, or selected from —C(O)NH—,

and

wherein each of said imidazolyl, benzimidazolyl or imidazopyridyl groupsare each optionally substituted; or a pharmaceutically acceptable saltthereof.
 4. The compound of claim 1, wherein: Y is C(O); R^(3a) ishydrogen; Q is hydrogen or

L is absent or selected from the group consisting of O, —C(O)NH—,—(C₁-C₄ alkyl)-NH—(C₁-C₄ alkyl)-, heterocyclic, C₂-C₄ alkenyl, or C₂-C₄alkynyl, each optionally substituted; A and B are each independentlyabsent, optionally substituted aryl, or optionally substitutedheteroaryl; or alternatively A, L and B are taken together to form alinker selected from one of the groups illustrated below:

wherein each of the above shown groups is each optionally substituted;at least one of A, B and L are present; and G and W are eachindependently —C(O)NH— or selected from one of the groups illustratedbelow:

wherein each of the above shown heteroaryl groups is each optionallysubstituted; Alternatively G and A are taken together to form atricyclic system selected from the following groups:

wherein each of the above shown heteroaryl groups is optionallysubstituted; and Alternatively W and B are taken together to form atricyclic system selected from the following groups:

wherein each of the above shown heteroaryl groups is optionallysubstituted; or a pharmaceutically acceptable salt thereof.
 5. Thecompound of claim 1, represented by Formula (IIIa), (IIIb), (IIIc) or(IIId):

wherein: R⁵ is hydrogen or optionally substituted C₁-C₄ alkyl; R⁶ ateach occurrence is independently C₁-C₈ alkyl optionally substituted withamino, halogen, hydroxy, protected amino, or optionally substitutedO(C₁-C₄ alkyl); A and B are each independently phenyl, monocyclicheteroaryl, bicyclic aryl, or bicyclic heteroaryl, each optionallysubstituted; L is O, NH, C(O), C(O)NH, C₁-C₄ alkyl, C₂-C₄ alkenyl, andC₂-C₄ alkynyl, (C₁-C₄ alkyl)-NH—(C₁-C₄ alkyl) and heterocyclic, eachoptionally substituted; L⁷ and L⁹ is each independently absent or alinear aliphatic group wherein at least one of L⁷ and L⁹ is present; X³and X⁴ at each occurrence are each independently N or C(R¹²); and R¹² ateach occurrence is independently hydrogen, halogen, hydroxy, optionallysubstituted C₁-C₄ alkyl or optionally substituted O(C₁-C₄ alkyl); or apharmaceutically acceptable salt thereof.
 6. The compound of claim 1,represented by Formula (IVa), (IVb), (IVc), (IVd), (IVe), or (IVf):

wherein: R⁵ is hydrogen or optionally substituted C₁-C₄ alkyl; R⁶ ateach occurrence is independently C₁-C₈ alkyl optionally substituted withamino, halogen, hydroxy, protected amino, aryl, heterocyclic, oroptionally substituted O(C₁-C₄ alkyl); A, B and D are each independentlyphenyl, monocyclic heteroaryl, bicyclic aryl, or bicyclic heteroaryl,each optionally substituted; L is O, NH, C(O), C(O)NH, C₁-C₄ alkyl,C₂-C₄ alkenyl, and C₂-C₄ alkynyl, (C₁-C₄ alkyl)-NH—(C₁-C₄ alkyl) andheterocyclic, each optionally substituted; L⁷ and L⁹ at each occurrenceare each independently absent or a linear aliphatic group, wherein atleast one of L⁷ and L⁹ is present; X³ and X⁴ at each occurrence isindependently N or C(R¹²); and R¹² at each occurrence is independentlyhydrogen, halogen, hydroxy, optionally substituted C₁-C₄ alkyl oroptionally substituted O(C₁-C₄ alkyl); or a pharmaceutically acceptablesalt thereof.
 7. The compound of claim 1, represented by Formula (Va),(Vb), (Vc), or (Vd):

wherein: L¹ and L³ are each independently absent or a linear aliphaticgroup wherein at least one of L¹ and L³ is present; L⁴ and L⁶ are eachindependently absent or a linear aliphatic group wherein at least one ofL⁴ and L⁶ is present; L⁷ and L⁹ at each occurrence are eachindependently absent or a linear aliphatic group, wherein at least oneof L⁷ and L⁹ is present; R⁵ is hydrogen or optionally substituted C₁-C₄alkyl; R⁶ at each occurrence is independently C₁-C₈ alkyl optionallysubstituted with amino, hydroxy, protected amino, aryl, heterocyclic, oroptionally substituted O(C₁-C₄ alkyl); U is CH₂, CHF, CHMe, CF₂, C═CH₂,C═CF₂, or C(R⁷)₂; R⁷ at each occurrence is independently selected fromthe group consisting of hydrogen, halogen, cyano, hydroxy, optionallysubstituted O(C₁-C₄ alkyl), amino optionally substituted with one or twoC₁-C₄ alkyl, optionally substituted C₁-C₄ alkyl and optionallysubstituted C₃-C₈ cycloalkyl; alternatively two geminal R⁷ groups aretaken together with the carbon to which they are attached to form aspiro, optionally substituted 3- to 7-membered cycloalkyl or 5- to7-membered heterocyclic; R^(7a) is hydrogen; and R^(7b) is hydrogen ormethyl; or alternatively R^(7a) and U or U and R^(7b) are taken togetherwith the carbon to which they are attached to form a fused, optionallysubstituted cyclopropyl, and the other of R^(7b) or R^(7a) is hydrogen;or yet alternatively U, R^(7a) and R^(7b) are taken together with thecarbon to which they are attached to form a bridged, optionallysubstituted C₄-C₇ cycloalkyl; or a pharmaceutically acceptable saltthereof.
 8. The compound of claim 1, represented by Formula (Ve), (Vf),(Vg) or (Vh):

wherein: L¹ and L³ are each independently absent or a linear aliphaticgroup wherein at least one of L¹ and L³ is present; L⁷ and L⁹ are eachindependently absent or a linear aliphatic group wherein at least one ofL⁷ and L⁹ is present; R⁵ is hydrogen or optionally substituted C₁-C₄alkyl; R⁶ at each occurrence is independently C₁-C₈ alkyl optionallysubstituted with amino, hydroxy, protected amino, aryl, heterocyclic, oroptionally substituted O(C₁-C₄ alkyl); U is CH₂, CHF, CHMe, CF₂, C═CH₂,C═CF₂, or C(R⁷)₂; R⁷ at each occurrence is independently selected fromthe group consisting of hydrogen, halogen, cyano, hydroxy, optionallysubstituted O(C₁-C₄ alkyl), amino optionally substituted with one or twoC₁-C₄ alkyl, optionally substituted C₁-C₄ alkyl and optionallysubstituted C₃-C₈ cycloalkyl; alternatively, two geminal R⁷ groups aretaken together with the carbon to which they are attached to form aspiro, optionally substituted 3- to 7-membered cycloalkyl or 5- to7-membered heterocyclic; R^(7a) is hydrogen; and R^(7b) is hydrogen ormethyl; or alternatively R^(7a) and U or U and R^(7b) are taken togetherwith the carbon to which they are attached to form a fused, optionallysubstituted cyclopropyl, and the other of R^(7b) or R^(7a) is hydrogen;or yet alternatively, U, R^(7a) and R^(7b) are taken together with thecarbon to which they are attached to form a bridged, optionallysubstituted C₄-C₇ cycloalkyl; or a pharmaceutically acceptable saltthereof.
 9. The compound of any one of claim 1, wherein

is selected from:

or a pharmaceutically acceptable salt thereof.
 10. The compound of claim1, wherein the linker -L¹-L²-L³- is selected from:

and the linker -L⁴-L⁵-L⁶- or -L⁷-L⁸-L⁹- R⁶— is selected from:

wherein R^(x) at each occurrence is independently hydrogen, amino,hydroxy, protected amino or O(C₁-C₄ alkyl); and R^(Y) at each occurrenceis independently hydrogen or optionally substituted C₁-C₈ alkyl; whereineach of the above shown groups is further optionally substituted; or apharmaceutically acceptable salt thereof.
 11. The compound of claim 1selected from the group of compounds 1-354 compiled in the followingtables: Compounds 1-219

Entry

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

Compounds 220-229

Entry R R′ R″ U 220 Me H H CH₂ 221 H H H CF₂ 222 Me H H S 223 H H H

224 H Me H CH₂ 225 H H H

226 H Ph H CH₂ 227 H H H

228 H H Ph CH₂ 229 H H H

Compounds 230-239

Entry R R′ R″ 230 Me H H 231 H CO₂Me H 232 H F H 233 H H CO₂Me 234 H H F235 H OMe H 236 H Cl H 237 H H OMe 238 H H Cl 239 H CF₃ H

Compounds 240-249

Entry R R′ R″ R′′′ 240 F H H H 241 F F H H 242 Me H H H 243 Me Me H H244 H H Me Me 245 H H Et Et 246 CF₃ H H H 247 CF₃ H CF₃ H 248 Cl H H H249 Cl H Cl H

Compounds 250-264

Entry R 250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

Compounds 265-282

Entry A^(a) 265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

Compounds 283-303

Entry A^(a) 283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

Compounds 304-315

Entry G^(g) 304

305

306

307

308

309

310

311

312

313

314

315

Compounds 316-333

Entry L^(a)—L^(b)—L^(c)—R^(d) 316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

Compounds 334-343

Compound 334

Compound 335

Compound 336

Compound 337

Compound 338

Compound 339

Compound 340

Compound 341

Compound 342

Compound 343

Compounds 344-346

Compound 344

Compound 345

Compound 346

Compounds 347-354

Compound 347

Compound 348

Compound 349

Compound 350

Compound 351

Compound 352

Compound 353

Compound 354


12. A pharmaceutical composition comprising a compound or a combinationof compounds according to claim 1 or a pharmaceutically acceptable saltthereof, in combination with a pharmaceutically acceptable carrier orexcipient.
 13. A method of inhibiting the replication of anRNA-containing virus comprising contacting said virus with atherapeutically effective amount of a compound or combination ofcompounds of claim 1, or a pharmaceutically acceptable salt thereof. 14.A method of treating or preventing infection caused by an RNA-containingvirus comprising administering to a patient in need of such treatment atherapeutically effective amount of a compound or combination ofcompounds of claim 1, or a pharmaceutically acceptable salt thereof. 15.The method of claim 14, wherein the RNA-containing virus is hepatitis Cvirus.
 16. The method of claim 14, further comprising the step ofco-administering one or more agents selected from the group consistingof a host immune modulator and an antiviral agent, or a combinationthereof.
 17. The method of claim 16, wherein the host immune modulatoris selected from the group consisting of interferon-alpha,pegylated-interferon-alpha, interferon-beta, interferon-gamma, consensusinterferon, a cytokine, and a vaccine.
 18. The method of claim 16,wherein the antiviral agents inhibit replication of HCV by inhibitinghost cellular functions associated with viral replication.
 19. Themethod of claim 16, wherein the antiviral agents inhibit the replicationof HCV by targeting proteins of the viral genome.
 20. The method ofclaim 16, wherein said antiviral agent is an inhibitor of a HCV viralprotein, a replication process or a combination thereof, wherein saidtargeting protein or replication process is selected from the groupconsisting of helicase, protease, polymerase, metalloprotease, NS4A,NS4B, NS5A, assembly, entry, and IRES.
 21. The method of claim 14,further comprising the step of co-administering an agent or combinationof agents that treat or alleviate symptoms of HCV infection selectedfrom cirrhosis and inflammation of the liver.
 22. The method of claim14, further comprising the step of co-administering one or more agentsthat treat patients for disease caused by hepatitis B (HBV) infection.23. The method of claim 14, further comprising the step ofco-administering one or more agents that treat patients for diseasecaused by human immunodeficiency virus (HIV) infection.
 24. Thepharmaceutical composition of claim 12, further comprising an agentselected from interferon, pegylated interferon, ribavirin, amantadine,an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV helicaseinhibitor, or an internal ribosome entry site inhibitor.
 25. Thepharmaceutical composition of claim 12, further comprising a cytochromeP450 monooxygenase inhibitor or a pharmaceutically acceptable saltthereof.
 26. The pharmaceutical composition of claim 25, wherein thecytochrome P450 mooxygenase inhibitor is ritonavir.
 27. A method oftreating hepatitis C infection in a subject in need thereof comprisingco-administering to said subject a cytochrome P450 monooxygenaseinhibitor or a pharmaceutically acceptable salt thereof, and a compoundof claim 1 or a pharmaceutically acceptable salt thereof.
 28. A processof making a compound according to claim 1 comprising: iv) preparing acompound of Formula (I-a-1):

via a transition-metal catalyzed cross-coupling reaction, ring-closuremetathesis or other intramolecular ring-closure reaction; wherein: W isan optionally substituted 5-membered heteroaryl containing one or morenitrogen or optionally substituted 5/6-membered fused heteroaryl,wherein the 5-membered ring of said 5/6-membered fused heteroarylcontains one or more nitrogen and is attached to the carbon atom towhich R³ is also attached, and wherein the 6-membered ring of said5/6-membered fused heteroaryl is attached to group B, L or A and is arylor heteroaryl; Q¹ is

Alternatively, G and Q¹ can be taken together to form a group selectedfrom:

X³ and X⁴ at each occurrence are each independently N or C(R¹²); and R¹²at each occurrence is independently hydrogen, halogen, hydroxy,optionally substituted C₁-C₄ alkyl or O(C₁-C₄ alkyl); Z^(a) isindependently an amino protecting group or —C(O)—R⁶; wherein R⁶ is C₁-C₈alkyl optionally substituted with amino, hydroxy, protected amino, orO(C₁-C₄ alkyl); and A, B, G, L, U, X¹, X², Y, L¹, L², L³, L⁴, L⁵, L⁶,L⁷, L⁸, L⁹, R¹, R^(3a), R⁵, R^(7a) and R^(7b) are as defined in claim 1;v) when Q¹ is

wherein Z^(a) is an amino protecting group, selectively deprotecting acompound of Formula (I-a-1) to give the corresponding amine of Formula(I-b-1):

and vi) Capping the released amino group of a compound of Formula(I-b-1) with LG-C(O)—R⁶, wherein LG is a leaving group; to give thecompound of Formula (I-c-1):


29. The process of claim 28, wherein the intramolecular ring-closurereaction is a type of Diels-Alder reaction, amide (lactam) formation,reductive amination, oximation, ester formation (lactonization),carbamate or urea formation.